Discovery and development of proton pump inhibitors
Encyclopedia
Proton pump inhibitors (PPIs) block the gastric Hydrogen potassium ATPase
(H+,K+-ATPase) and inhibit gastric acid secretion. These drugs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease
(GERD) and peptic ulcer disease.
was the final step in acid secretion. Literature from anaesthetic screenings led attention to the potential antiviral compound pyridylthioacetamide which after further examination pointed the focus on an anti-secretory compound with unknown mechanisms of action called timoprazole. Timoprazole is a pyridylmethylsulfinyl benzimidazole
and appealed due to its simple chemical structure and its surprisingly high level of anti-secretory activity.
Optimization of substituted benzimidazoles and their antisecretory effects where studied on the newly discovered proton pump to obtain higher pKa
values of the pyridine
, thereby facilitating accumulation within the parietal cell and increasing the rate of acid-mediated conversion to the active mediate. As a result of such optimization the first proton pump inhibiting drug was released on the market, omeprazole, a proton pump inhibitor (PPI). Other PPIs like lansoprazole and pantoprazole would follow in its footsteps, claiming their share of a flourishing market, after their own course of development.
Proton pump inhibitors are prodrugs and their actual inhibitory form is somewhat controversial. In acidic solution, the sulfenic acid
is isolated before reaction with one or more cysteines accessible from the luminar
surface of the enzyme
, a tetracyclic sulfenamide. This is a planar molecule thus any enantiomer of a PPI loses stereospecifity upon activation.
The effectiveness of these drugs derives from 2 factors: their target, the H+,K+-ATPase which is responsible for the last step in acid secretion; therefore, their action on acid secretion is independent of the stimulus to acid secretion, of histamine
, acetylcholine
, or other yet to be discovered stimulants. Also, their mechanism of action involves covalent binding of the activated drug to the enzyme, resulting in a duration of action that exceeds their plasma half-life
.
results in a median diurnal
pH
of 1.4. This very large (>106 -fold) H+ gradient
, is generated by the gastric H+,K+-ATPase which is a ATP-driven proton pump. Hydrolysis of one ATP molecule is used to catalyse the electroneutral exchange of two luminal potassium
ions for two cytoplasmic protons through the gastric membrane.
domain
of the β subunit contains six or seven N-linked glycosylation
sites which is important for the enzyme assembly, maturation
and sorting
.
states, E1 and E2. The cytoplasmic-open E1 and luminal-open E2 states have high affinity for H+ and K+. The expulsion of the proton at 160 mM
(pH 0.8) concentration
results from movement of lysine
791 into the ion
binding site in the E2P configuration.
of iodine
uptake as well as atrophy
of the thymus
gland. A literature search showed that some substituted mercapto-benzimidazoles, had no effect on iodine uptake and introduction of such substituents into timoprazole resulted in an elimination of the toxic effects, without reducing the antisecretory effect. A derivative of timoprazole, omeprazole, was discovered in 1979, and was the first of a new class of drug that control acid secretion in the stomach, a proton pump inhibitor (PPI). Addition of 5-methoxy-substitution to the benzimidazole moiety of omeprazole was also made and gave the compound much more stability at neutral pH. In 1980, an Investigational New Drug (IND) application was filed and omeprazole was taken into Phase III human trials in 1982. A new approach for the treatment of acid-related diseases was introduced, and Omeprazole was quickly shown to be clinically superior to the histamine H2 receptor antagonist
s, and was launced in 1988 as Losec® in Europe, and in 1990 as Prilosec® in the United States. In 1996, Losec® became the world's biggest ever selling pharmaceutical, and by 2004 over 800 million patients had been treated with the drug worldwide. During 1980s, about 40 other companies entered the PPIs area, but few achieved market success: Takeda with lansoprazole, Byk Gulden with pantoprazole, and Eisai with rabeprazole, all of which were analogues of omeprazole.
group to the benzimidazole moiety led to a series of very active compounds with varying solution-stability. In general fluoro substituents were found to block metabolism
at the point where they were attached. Later the more balanced fluoroalkoxy substituent, instead of the highly lipophilic
and strongly electron-withdrawing trifluoromethyl substituent, led to highly active compounds with supposed longer half-lives and higher solution stability.
It was realized that activity was somehow linked to instability in solution and then came to the conclusion that the cyclic sulfenamides, formed in acidic conditions, were the active principle of the PPIs. Finally, it was understood that seemingly small alterations in the backbone of timoprazole led nowhere, and focus had to be centered on the substituents on the backbone. However, necessary intramolecular rearrangement of the benzimidazole into sulfenamide posed severe geometric constraints. Optimal compounds would be those that were stable at neutral pH but were quickly activated at low pH.
A clear-cut design of active inhibitors was still not possible because in the complex multi-step chemistry the influence of a substituent on each step in the cascade could be different, and therefore not predictable for the overall rate of the prerequisite acid activation. Smith Kline and French, that entered into collaboration with Byk Gulden mid-1984, greatly assisted in determining criteria for further development. From 1985, the aim was to identify a compound with good stability at neutral pH, sustaining this higher level of stability down to pH 5 but being rapidly activateable at lower pHs, combined with a high level of H+/K+-ATPase inhibition. From the numerous already synthesized and tested compounds that fulfilled these criteria the most promising candidates were pantoprazole and its salt, pantoprazole sodium.
In 1986 pantoprazole sodium sesquihydrate was synthesized and from 1987 onwards the development of pantoprazole was switched to the sodium salt which is more stable and has better compatibility with other excipients used in the drug formulation.
Pantoprazole was identified after nearly seven years of research and registered for clinical use after a further seven years of development, and finally reached its first market in 1994 in Germany. During the course of the studies on pantoprazole, more than 650 PPIs had been synthesized and evaluated. Pantoprazole obtained high selection criteria in its development process – especially concerning the favorable low potential for interaction with other drugs. Good solubility of Pantoprazole and a very high solution stability allowed it to become the first marketed PPI for intravenous use in critical care patients.
Omeprazole was the first PPI on the market, in 1988. It is a 1:1 racemate drug with a backbone structure of timoprazole, but substituted with two methoxy and two methyl groups. One of the methoxy group is at position 6 of the bensoimidazole and the other at position 4 of the pyridine and the methyl groups are at position 3 and 5 of the pyridine.
Omeprazole is available as enteric-coated tablets, capsules, chewable tablets, powder
for oral suspensions and powder for intravenous injection.
Lansoprazole was the second of the PPI drugs to reach the market, being launched in Europe in 1991 and the US in 1995.
It has no substitutions at the bensimidazole but two substituents on the pyridine, methyl group at position 3 and a trifluoroethoxy group at position 4. The drug is a 1:1 racemate of the enantiomers dexlansoprazole and levolansoprazole. It is available in gastroresistant capsules and tablets as well as chewable tablets.
Pantoprazole was the third PPI and was introduced to the German market in 1994.
It has a difluoroalkoxy sidegroup on the bensimidazole part and two methoxy groups in position 3 and 4 on the pyridine.
Pantoprazole was first prepared in April 1985 by a small group of scale-up chemists. It is a dimethoxy-substituted pyridine bound to a fluoroalkoxy substituted benzimidazole.
Pantoprazole-sodium is available as gastroresistant or delayed release tablets and as lyophilized powder for intravenous use.
Rabeprazole is a novel bensimidazole compound on market, since 1999 in USA. It is similar to lansoprazole in having no substituents on its bensimidazole part and a methyl group at site 3 on the pyridine, the only difference is the methoxypropoxy substitution at site 4 instead of the trifluoroethoxy group on lansoprazole.
Rabeprazole is marketed as rabeprazole sodium salt. It is available as enteric-coated tablets.
In 2001 esomeprazole was launched in USA, as a follow-up of omeprazoles patent.
Esomeprazole is the S-enantiomer of omeprazole and provides higher bioavailability
and improved efficacy
, in terms of stomach acid control, over the R-enantiomer of omeprazole. In theory, by using pure esomeprazole the effects on the proton pump will be equal in all patients, eliminating the "poor metabolizer effect" of the racemate omeprazole. It is available as delayed-release capsules or tablets and as esomeprazole sodium for intravenous injection/infusion. Oral esomeprazole preparations are enteric-coated, due to the rapid degradation of the drug in the acidic condition of the stomach. This is achieved by formulating capsules using the multiple-unit pellet system.
Although the (S)-isomer
is more potent in humans, the (R)-isomer is more potent in testings of rats, while the enantiomers are equipotent in dogs.
Dexlansoprazole was launched as a follow up of lansoprazole in 2009.
Dexlansoprazole is an R-enantiomer of lansoprazole, marketed as Dexilant. After oral appliance of the racemic lansoprazole, the circulating drug is 80% dexlansoprazole. Moreover, both enantiomers have similar effects on the proton pump. Consequently, the main advantage of Dexilant is not the fact that it is an enantiopure substance. The advantage is the pharmaceutical formulation of the drug, which is based on a dual release technology, with the first quick release producing a blood plasma
peak concentration about one hour after application, and the second retarded release producing another peak about four hours later.
Tenatoprazole (TU-199), an imidazopyridine proton pump inhibitor, is a novel compound that has been designed as a new chemical entity with a substantially prolonged plasma half-life (7h), but otherwise has similar activity as other PPIs.
The difference in the structural backbone of tenatoprazole compared to bensimidazole PPIs, is its imidazo[4,5-b]pyridine moiety, which reduces the rate of metabolism, allowing a longer plasma residence time but also decreases the pKa of the fused imidazole N as compared to the current PPIs. Tenatoprazole has the same substituents as omeprazole, the methoxy groups at position 6 on the imidazopyridine and at position 4 on the pyridine part as well as two methyl groups at position 3 and 5 on the pyridine.
The bioavailability of tenatoprazole is double for the S-tenatoprazole sodium salt hydrate
form when compared to the free form in dogs. This increased bioavailability is due to differences in the crystal structure
and hydrophobic nature of the two forms, and therefore its more likely to be marketed as the pure S-enantiomer.
All PPIs react with cysteine 813 in the loop between TM5 and TM6 on the H+,K+-ATPase, fixing the enzyme in the E2 configuration. Omeprazole reacts with cysteine 813 and 892. Rabeprazole binds to cysteine 813 and both 892 and 321. Lansoprazole reacts with cysteine 813 and cysteine 321, whereas pantoprazole and tenatoprazole react with cysteine 813 and 822.
Reaction
with cysteine 822 confers a rather special property to the covalently inhibited enzyme, namely irreversibility
to reducing agents. The likely first step is binding of the prodrug protonated on the pyridine of the compound with cysteine 813. Then the second proton is added with acid transport by the H+,K+-ATPase, and the compound is activated. Recent data suggest the hydrated sulfenic acid to be the reactive species forming directly from the mono-protonated benzimidazole bound on the surface of the pump.
, giving a concentration at the luminal surface of the pump that is about, 1000 fold of that in the blood. The second vital step is pH-dependent conversion from the accumulated prodrug to the activated species that is a highly reactive thiophilic reagent. This means that a second protonation of these compounds is required for their activation to the compounds that form disulfides with luminally accessible cysteines of the H+,K+-ATPase. The order of acid stability is from highest to lowest tenatoprazole, pantoprazole, omeprazole, lansoprazole, rabeprazole.
Three factors of primary importance: a) the unique location of the H+,K+-ATPase, and specific action of PPIs; b) the concentration of the protonated form of PPIs in the acidic canaliculus; and c) the conversion of PPIs in the acidic compartments close to their target enzyme, the H+,K+-ATPase.
is probably due to the effect of the endogenous
antioxidant
glutathione
which leads to the release of omeprazole sulfide and reactivation of the enzyme.
Differing pyridine and benzimidazole substituents result in small, but potentially significant different physical and chemical properties.
Direct comparison of pantoprazole-sodium with other anti-secretory drugs showed that it was significantly more effective than H2-receptor antagonists and either equivalent or better than other clinically used PPIs. Another study states rabeprazole undergoes activation over a greater pH range than omeprazole, lansoprazole, and pantoprazole, and converts to the sulphenamide form more rapidly than any of these three drugs.
Most oral PPI preparations are enteric-coated, due to the rapid degradation of the drugs in the acidic conditions of the stomach. For example omeprazole is unstable in acid with a half-life of 2 min at pH 1-3, but is significantly more stable at pH 7 (half-life ca. 20 h).
The acid protective coating prevents conversion to the active principle in the lumen of the stomach, which then will react with any available sulfhydryl group in food and will not penetrate to the lumen of the secretory canaliculus
The oral bioavailability of PPIs is high; 77% for pantoprazole, 80-90% for lansoprazole and 89% for esomeprazole. All the PPIs except tenatoprazole are rapidly metabolized in the liver by CYP enzymes, mostly by CYP 2C19 and CYP 3A4. PPIs are sensitive to CYP enzymes and have different pharmacokinetic profiles. Studies comparing the efficacy of PPIs indicate that esomeprazole and tenatoprazole have stronger acid suppression, with a longer period of intragastric pH (pH > 4).
Studies of the effect of tenatoprazole on acid secretion in in vivo animal models, such as pylorus-ligated rats and acute gastric fistula rats, demonstrated a 2–4-fold more potent inhibitory activity compared with omeprazole. A more potent inhibitory activity was also shown in several models of induced gastric lesions. In Asian as well as Caucasian healthy subjects, tenatoprazole exhibited a sevenfold longer half-life than the existing H+,K+-ATPase inhibitors. It is thus hypothesized that a longer half-life results in a more prolonged inhibition of gastric acid secretion, especially during the night.
A strong relationship has been stated between the degree and duration of gastric acid inhibition, as measured by monitoring of the 24-h intragastric pH in pharmacodynamic studies, and the rate of healing and symptom relief reported.
A clinical study showed that nocturnal acid breakthrough duration was significantly shorter for 40 mg of tenatoprazole than for 40 mg of esomeprazole, with the conclusion that tenatoprazole was significantly more potent than esomeprazole during the night. Although, the therapeutic relevance of this pharmacological advantage deserves further study.
PPIs have been used successfully in triple-therapy regiments with clarithromycin and amoxicillin for the eradication of H.pylori with no significant difference between different PPI-based regimens.
, there is still room for improvement in the speed of onset of acid suppression as well as mode of action that is independent of an acidic environment and also better inhibition of the proton pump. Therefore, a new class of PPIs, potassium-competitive acid blockers or acid pump antagonists, have been under development the past years and will most likely be the next generation of drugs that suppress gastric activity. These new agents can in a reversible and competitive fashion inhibit the final step in the gastric acid secretion with respect to K+ binding to the parietal cell gastric H+,K+-ATPase. That is, they block the action of the H+,K+-ATPase by binding to or near the site of the K+ channel. Since the binding is competitive and reversible these agents have the potential to achieve faster inhibition of acid secretion and longer duration of action compared to PPIs, resulting in quicker symptom relief and healing. The imidazopyridine based compound SCH28080 was the prototype of this class, and turned out to be hepatotoxic. Newer agents that are currently in development include CS-526, soraprazan and raveprazan in which the latter have reached clinical trials. Studies remain to determine whether these or other related compounds can become useful.
Other activity that PPIs may modulate is v-type H+-ATPase activity, which is widely distributed in a variety of cells in the human body. Among these, the acid-producing systems in osteoclasts and leukocytes are well developed for maintaining bone turnover and exhibit bactericidal roles and promote tissue-destructive inflammation. Hence, there is still much potential for research on the pharmacological and clinical aspects of PPI treatment.
Hydrogen potassium ATPase
Gastric hydrogen potassium ATPase is also known as H+/K+ ATPase- Function and location :The gastric hydrogen potassium ATPase or H+/K+ ATPase is the proton pump of the stomach and, as such, is the enzyme primarily responsible for the acidification of the stomach contents...
(H+,K+-ATPase) and inhibit gastric acid secretion. These drugs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease
Gastroesophageal reflux disease
Gastroesophageal reflux disease , gastro-oesophageal reflux disease , gastric reflux disease, or acid reflux disease is chronic symptoms or mucosal damage caused by stomach acid coming up from the stomach into the esophagus...
(GERD) and peptic ulcer disease.
History
Evidence emerged by the end of the 1970s that the newly discovered proton pump (H+,K+-ATPase) in the secretory membrane of the parietal cellParietal cell
Parietal cells, or oxyntic cells, are the stomach epithelium cells that secrete gastric acid and intrinsic factor.Acetylcholine and gastrin . The histamine receptors act by increasing intracellular cAMP, whereas the muscarinic and gastrin receptors increase intracellular Ca2+ levels...
was the final step in acid secretion. Literature from anaesthetic screenings led attention to the potential antiviral compound pyridylthioacetamide which after further examination pointed the focus on an anti-secretory compound with unknown mechanisms of action called timoprazole. Timoprazole is a pyridylmethylsulfinyl benzimidazole
Benzimidazole
Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound consists of the fusion of benzene and imidazole. The most prominent benzimidazole compound in nature is N-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12. Benzimidazole, in...
and appealed due to its simple chemical structure and its surprisingly high level of anti-secretory activity.
Optimization of substituted benzimidazoles and their antisecretory effects where studied on the newly discovered proton pump to obtain higher pKa
PKA
PKA, pKa, or other similar variations may stand for:* pKa, the symbol for the acid dissociation constant at logarithmic scale* Protein kinase A, a class of cAMP-dependent enzymes* Pi Kappa Alpha, the North-American social fraternity...
values of the pyridine
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...
, thereby facilitating accumulation within the parietal cell and increasing the rate of acid-mediated conversion to the active mediate. As a result of such optimization the first proton pump inhibiting drug was released on the market, omeprazole, a proton pump inhibitor (PPI). Other PPIs like lansoprazole and pantoprazole would follow in its footsteps, claiming their share of a flourishing market, after their own course of development.
Basic structure
PPIs can be split into two groups based on their basic structure. Though all have a substituted pyridine part, one group has it linked to various bensimidazoles but the other has it linked to a substituted imidazopyridine. All marketed PPIs (omeprazole, lansoprazole, pantoprazole etc.) are in the benzimidazole group.Proton pump inhibitors are prodrugs and their actual inhibitory form is somewhat controversial. In acidic solution, the sulfenic acid
Sulfenic acid
A sulfenic acid is an organosulfur compound and oxoacid with the general formula RSOH, where R ≠ H. Simple sulfenic acids, such as methanesulfenic acid, CH3SOH, are highly reactive and cannot be isolated in solution. In the gas phase the lifetime of methanesulfenic acid is about one minute...
is isolated before reaction with one or more cysteines accessible from the luminar
Luminar
Luminar can be:*An Animorphs species*Luminar Leisure, a UK based company that operates bars and nightclubs....
surface of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
, a tetracyclic sulfenamide. This is a planar molecule thus any enantiomer of a PPI loses stereospecifity upon activation.
The effectiveness of these drugs derives from 2 factors: their target, the H+,K+-ATPase which is responsible for the last step in acid secretion; therefore, their action on acid secretion is independent of the stimulus to acid secretion, of histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
, acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
, or other yet to be discovered stimulants. Also, their mechanism of action involves covalent binding of the activated drug to the enzyme, resulting in a duration of action that exceeds their plasma half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
.
The Gastric ATPase
Acid secretion by the human stomachStomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
results in a median diurnal
Diurnal cycle
A diurnal cycle is any pattern that recurs every 24 hours as a result of one full rotation of the Earth.In climatology, the diurnal cycle is one of the most basic forms of climate patterns. The most familiar such pattern is the diurnal temperature variation...
pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
of 1.4. This very large (>106 -fold) H+ gradient
Gradient
In vector calculus, the gradient of a scalar field is a vector field that points in the direction of the greatest rate of increase of the scalar field, and whose magnitude is the greatest rate of change....
, is generated by the gastric H+,K+-ATPase which is a ATP-driven proton pump. Hydrolysis of one ATP molecule is used to catalyse the electroneutral exchange of two luminal potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
ions for two cytoplasmic protons through the gastric membrane.
Structure
The proton pump, H+,K+-ATPase is a α,β-heterodimeric enzyme. The catalytic α subunit has ten transmembrane segments with a cluster of intramembranal carboxylic amino acids located in the middle of the transmembrane segments TM4, TM5, TM6 and TM8. The β subunit has one transmembrane segment with N terminus in cytoplasmic region. The extracellularExtracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
domain
Integral membrane protein
An integral membrane protein is a protein molecule that is permanently attached to the biological membrane. Proteins that cross the membrane are surrounded by "annular" lipids, which are defined as lipids that are in direct contact with a membrane protein...
of the β subunit contains six or seven N-linked glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
sites which is important for the enzyme assembly, maturation
Maturation
Maturation could refer to any of the following:* Fetal development* Developmental biology* Emotional development* Or physical maturation of any biological life form - see individual articles for maturation of different life forms....
and sorting
Sorting
Sorting is any process of arranging items in some sequence and/or in different sets, and accordingly, it has two common, yet distinct meanings:# ordering: arranging items of the same kind, class, nature, etc...
.
Function
The ion transport is accomplished by cyclical conformational changes of the enzyme between its two main reactionChemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...
states, E1 and E2. The cytoplasmic-open E1 and luminal-open E2 states have high affinity for H+ and K+. The expulsion of the proton at 160 mM
MM
-Computers:* .mm, the Myanmar's Internet country code top-level domain* mm tree, the Andrew Morton's Linux kernel tree* Columbia MM, an early e-mail client* MediaMonkey, a digital media player and media library application-File extension :...
(pH 0.8) concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
results from movement of lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
791 into the ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
binding site in the E2P configuration.
Discovery
In the year 1975, timoprazole was found to inhibit acid secretion irrespective of stimulus, extracellular or intracellular. Studies on timoprazole revealed enlargement of the thyroid gland due to inhibitionEnzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of iodine
Iodine
Iodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....
uptake as well as atrophy
Atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...
of the thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
gland. A literature search showed that some substituted mercapto-benzimidazoles, had no effect on iodine uptake and introduction of such substituents into timoprazole resulted in an elimination of the toxic effects, without reducing the antisecretory effect. A derivative of timoprazole, omeprazole, was discovered in 1979, and was the first of a new class of drug that control acid secretion in the stomach, a proton pump inhibitor (PPI). Addition of 5-methoxy-substitution to the benzimidazole moiety of omeprazole was also made and gave the compound much more stability at neutral pH. In 1980, an Investigational New Drug (IND) application was filed and omeprazole was taken into Phase III human trials in 1982. A new approach for the treatment of acid-related diseases was introduced, and Omeprazole was quickly shown to be clinically superior to the histamine H2 receptor antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
s, and was launced in 1988 as Losec® in Europe, and in 1990 as Prilosec® in the United States. In 1996, Losec® became the world's biggest ever selling pharmaceutical, and by 2004 over 800 million patients had been treated with the drug worldwide. During 1980s, about 40 other companies entered the PPIs area, but few achieved market success: Takeda with lansoprazole, Byk Gulden with pantoprazole, and Eisai with rabeprazole, all of which were analogues of omeprazole.
Development of Pantoprazole
The story of pantoprazoles discovery is a good example of the stepwise development of PPIs. The main focus of modification of timoprazole was the benzimidazole part of its structure. Addition of a trifluoromethylTrifluoromethyl
Trifluoromethyl is a functional group in organofluorines that has the formula -CF3. The naming of is group is derived from the methyl group , by replacing each hydrogen atom by a fluorine atom. The trifluomethyl group has a significant electronegativity that is often described as being...
group to the benzimidazole moiety led to a series of very active compounds with varying solution-stability. In general fluoro substituents were found to block metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
at the point where they were attached. Later the more balanced fluoroalkoxy substituent, instead of the highly lipophilic
Lipophilic
Lipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...
and strongly electron-withdrawing trifluoromethyl substituent, led to highly active compounds with supposed longer half-lives and higher solution stability.
It was realized that activity was somehow linked to instability in solution and then came to the conclusion that the cyclic sulfenamides, formed in acidic conditions, were the active principle of the PPIs. Finally, it was understood that seemingly small alterations in the backbone of timoprazole led nowhere, and focus had to be centered on the substituents on the backbone. However, necessary intramolecular rearrangement of the benzimidazole into sulfenamide posed severe geometric constraints. Optimal compounds would be those that were stable at neutral pH but were quickly activated at low pH.
A clear-cut design of active inhibitors was still not possible because in the complex multi-step chemistry the influence of a substituent on each step in the cascade could be different, and therefore not predictable for the overall rate of the prerequisite acid activation. Smith Kline and French, that entered into collaboration with Byk Gulden mid-1984, greatly assisted in determining criteria for further development. From 1985, the aim was to identify a compound with good stability at neutral pH, sustaining this higher level of stability down to pH 5 but being rapidly activateable at lower pHs, combined with a high level of H+/K+-ATPase inhibition. From the numerous already synthesized and tested compounds that fulfilled these criteria the most promising candidates were pantoprazole and its salt, pantoprazole sodium.
In 1986 pantoprazole sodium sesquihydrate was synthesized and from 1987 onwards the development of pantoprazole was switched to the sodium salt which is more stable and has better compatibility with other excipients used in the drug formulation.
Pantoprazole was identified after nearly seven years of research and registered for clinical use after a further seven years of development, and finally reached its first market in 1994 in Germany. During the course of the studies on pantoprazole, more than 650 PPIs had been synthesized and evaluated. Pantoprazole obtained high selection criteria in its development process – especially concerning the favorable low potential for interaction with other drugs. Good solubility of Pantoprazole and a very high solution stability allowed it to become the first marketed PPI for intravenous use in critical care patients.
Development of Esomeprazole
Omeprazole showed an inter-individual variability and therefore a significant number of patients with acid-related disorders required higher or multiple doses to achieve symptom relief and healing. Astra started a new research program in 1987 to identify a new analogue to omeprazole with less interpatient variability. Only one compound proved superior to omeprazole and that was the S-isomer, esomeprazole, which was developed as the magnesium salt. Esomeprazole magnesium (Nexium®), received its first approval in 2000 and provided more pronounced inhibition of acid secretion and less inter-patient variation compared to omeprazole. In 2004, Nexium®, had already been used to treat over 200 million patients.Bensimidazoles
- OmeprazoleOmeprazoleOmeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...
(brand names: Losec, Prilosec, Zegerid, ocid, Lomac, Omepral, Omez)
Omeprazole was the first PPI on the market, in 1988. It is a 1:1 racemate drug with a backbone structure of timoprazole, but substituted with two methoxy and two methyl groups. One of the methoxy group is at position 6 of the bensoimidazole and the other at position 4 of the pyridine and the methyl groups are at position 3 and 5 of the pyridine.
Omeprazole is available as enteric-coated tablets, capsules, chewable tablets, powder
Powder (substance)
A powder is a dry,thick bulk solid composed of a large number of very fine particles that may flow freely when shaken or tilted. Powders are a special sub-class of granular materials, although the terms powder and granular are sometimes used to distinguish separate classes of material...
for oral suspensions and powder for intravenous injection.
- LansoprazoleLansoprazoleLansoprazole is a proton-pump inhibitor which prevents the stomach from producing gastric acid. It is manufactured by a number of companies worldwide under several brand names . It was first approved by the U.S...
(brand names: Prevacid, Zoton, Inhibitol, Levant, Lupizole)
Lansoprazole was the second of the PPI drugs to reach the market, being launched in Europe in 1991 and the US in 1995.
It has no substitutions at the bensimidazole but two substituents on the pyridine, methyl group at position 3 and a trifluoroethoxy group at position 4. The drug is a 1:1 racemate of the enantiomers dexlansoprazole and levolansoprazole. It is available in gastroresistant capsules and tablets as well as chewable tablets.
- PantoprazolePantoprazolePantoprazole is a proton pump inhibitor drug that inhibits gastric acid secretion.-Use:...
(brand names: Protonix, Somac, Pantoloc, Pantozol, Zurcal, Zentro, Pan)
Pantoprazole was the third PPI and was introduced to the German market in 1994.
It has a difluoroalkoxy sidegroup on the bensimidazole part and two methoxy groups in position 3 and 4 on the pyridine.
Pantoprazole was first prepared in April 1985 by a small group of scale-up chemists. It is a dimethoxy-substituted pyridine bound to a fluoroalkoxy substituted benzimidazole.
Pantoprazole-sodium is available as gastroresistant or delayed release tablets and as lyophilized powder for intravenous use.
- RabeprazoleRabeprazoleRabeprazole is an antiulcer drug in the class of proton pump inhibitors. It was developed by Eisai Co. and is marketed by Janssen-Cilag as rabeprazole sodium under the brand names AcipHex in the US and Pariet in Britain, Italy, Greece, Australia, Brazil, Canada, Japan, and Russia. It is sold as...
(brand names: Zechin, Rabecid, Nzole-D, AcipHex, Pariet, Rabeloc)
Rabeprazole is a novel bensimidazole compound on market, since 1999 in USA. It is similar to lansoprazole in having no substituents on its bensimidazole part and a methyl group at site 3 on the pyridine, the only difference is the methoxypropoxy substitution at site 4 instead of the trifluoroethoxy group on lansoprazole.
Rabeprazole is marketed as rabeprazole sodium salt. It is available as enteric-coated tablets.
- EsomeprazoleEsomeprazoleEsomeprazole is a proton pump inhibitor developed and marketed by AstraZeneca which is used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease and Zollinger-Ellison syndrome...
(brand names: Nexium, Esotrex)
In 2001 esomeprazole was launched in USA, as a follow-up of omeprazoles patent.
Esomeprazole is the S-enantiomer of omeprazole and provides higher bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
and improved efficacy
Efficacy
Efficacy is the capacity to produce an effect. It has different specific meanings in different fields. In medicine, it is the ability of an intervention or drug to reproduce a desired effect in expert hands and under ideal circumstances.- Healthcare :...
, in terms of stomach acid control, over the R-enantiomer of omeprazole. In theory, by using pure esomeprazole the effects on the proton pump will be equal in all patients, eliminating the "poor metabolizer effect" of the racemate omeprazole. It is available as delayed-release capsules or tablets and as esomeprazole sodium for intravenous injection/infusion. Oral esomeprazole preparations are enteric-coated, due to the rapid degradation of the drug in the acidic condition of the stomach. This is achieved by formulating capsules using the multiple-unit pellet system.
Although the (S)-isomer
Isomer
In chemistry, isomers are compounds with the same molecular formula but different structural formulas. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical...
is more potent in humans, the (R)-isomer is more potent in testings of rats, while the enantiomers are equipotent in dogs.
- DexlansoprazoleDexlansoprazoleDexlansoprazole is a proton pump inhibitor that is marketed by Takeda Pharmaceuticals. Chemically, it is an enantiomer of lansoprazole. The compound was launched in the US for use in the treatment and maintenance of patients with erosive oesophagitis and non-erosive gastro-oesophageal reflux disease...
(brand name: Kapidex, Dexilant)
Dexlansoprazole was launched as a follow up of lansoprazole in 2009.
Dexlansoprazole is an R-enantiomer of lansoprazole, marketed as Dexilant. After oral appliance of the racemic lansoprazole, the circulating drug is 80% dexlansoprazole. Moreover, both enantiomers have similar effects on the proton pump. Consequently, the main advantage of Dexilant is not the fact that it is an enantiopure substance. The advantage is the pharmaceutical formulation of the drug, which is based on a dual release technology, with the first quick release producing a blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
peak concentration about one hour after application, and the second retarded release producing another peak about four hours later.
Imidazopyridines
- TenatoprazoleTenatoprazoleTenatoprazole , discovered in Japan, is a proton pump inhibitor indicated for the treatment of reflux oesophagitis and peptic ulcer. Discovered by Mitsubishi Pharma, it is an imidazopyridine derivative and has an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump...
Tenatoprazole (TU-199), an imidazopyridine proton pump inhibitor, is a novel compound that has been designed as a new chemical entity with a substantially prolonged plasma half-life (7h), but otherwise has similar activity as other PPIs.
The difference in the structural backbone of tenatoprazole compared to bensimidazole PPIs, is its imidazo[4,5-b]pyridine moiety, which reduces the rate of metabolism, allowing a longer plasma residence time but also decreases the pKa of the fused imidazole N as compared to the current PPIs. Tenatoprazole has the same substituents as omeprazole, the methoxy groups at position 6 on the imidazopyridine and at position 4 on the pyridine part as well as two methyl groups at position 3 and 5 on the pyridine.
The bioavailability of tenatoprazole is double for the S-tenatoprazole sodium salt hydrate
Hydrate
Hydrate is a term used in inorganic chemistry and organic chemistry to indicate that a substance contains water. The chemical state of the water varies widely between hydrates, some of which were so labeled before their chemical structure was understood....
form when compared to the free form in dogs. This increased bioavailability is due to differences in the crystal structure
Crystal structure
In mineralogy and crystallography, crystal structure is a unique arrangement of atoms or molecules in a crystalline liquid or solid. A crystal structure is composed of a pattern, a set of atoms arranged in a particular way, and a lattice exhibiting long-range order and symmetry...
and hydrophobic nature of the two forms, and therefore its more likely to be marketed as the pure S-enantiomer.
PPIs binding mode
The disulfide binding of the inhibitor takes place in the luminal sector of the H+,K+-ATPase were 2 mol of inhibitor is bound per 1 mol of active site H+,K+-ATPase.All PPIs react with cysteine 813 in the loop between TM5 and TM6 on the H+,K+-ATPase, fixing the enzyme in the E2 configuration. Omeprazole reacts with cysteine 813 and 892. Rabeprazole binds to cysteine 813 and both 892 and 321. Lansoprazole reacts with cysteine 813 and cysteine 321, whereas pantoprazole and tenatoprazole react with cysteine 813 and 822.
Reaction
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...
with cysteine 822 confers a rather special property to the covalently inhibited enzyme, namely irreversibility
Irreversibility
In science, a process that is not reversible is called irreversible. This concept arises most frequently in thermodynamics, as applied to processes....
to reducing agents. The likely first step is binding of the prodrug protonated on the pyridine of the compound with cysteine 813. Then the second proton is added with acid transport by the H+,K+-ATPase, and the compound is activated. Recent data suggest the hydrated sulfenic acid to be the reactive species forming directly from the mono-protonated benzimidazole bound on the surface of the pump.
Mechanism of action
PPIs are weak bases with a pKa1 between 3.8 and 4.5 and accumulate in the acidic space of the secretory canaliculus of the stimulated parietal cell (pH ~1.0). The acid space-dependent concentration of the PPIs is the first important property that determines their therapeutic indexTherapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
, giving a concentration at the luminal surface of the pump that is about, 1000 fold of that in the blood. The second vital step is pH-dependent conversion from the accumulated prodrug to the activated species that is a highly reactive thiophilic reagent. This means that a second protonation of these compounds is required for their activation to the compounds that form disulfides with luminally accessible cysteines of the H+,K+-ATPase. The order of acid stability is from highest to lowest tenatoprazole, pantoprazole, omeprazole, lansoprazole, rabeprazole.
Three factors of primary importance: a) the unique location of the H+,K+-ATPase, and specific action of PPIs; b) the concentration of the protonated form of PPIs in the acidic canaliculus; and c) the conversion of PPIs in the acidic compartments close to their target enzyme, the H+,K+-ATPase.
Half-life of PPIs
PPIs have a rather short half-life in human plasma (60-90 min), but because they covalently bind to the pump, their half-life of inhibition of gastric acid secretion is substantially longer. The half-life at the site of action is estimated to be approximately 24h. Dissociation of the inhibitory complexProtein complex
A multiprotein complex is a group of two or more associated polypeptide chains. If the different polypeptide chains contain different protein domain, the resulting multiprotein complex can have multiple catalytic functions...
is probably due to the effect of the endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
which leads to the release of omeprazole sulfide and reactivation of the enzyme.
Saturation of the gastric ATPase
Even though consumption of food stimulates acid secretion and acid secretion activates PPIs, PPIs cannot inhibit all pumps. About 70% of pump enzyme is inhibited, as PPIs have a short half-life and not all pump enzymes are activated. It takes about 3 days to reach steady-state inhibition of acid secretion, as a balance is struck between covalent inhibition of active pumps, subsequent stimulation of inactive pumps after the drug has been eliminated from the blood, and de novo synthesis of new pumps.Clinical pharmacology of PPIs
Although these drugs omeprazole, lansoprazole, pantoprazole, and rabeprazole share common structure and mode of action, each differs somewhat in its clinical pharmacology.Differing pyridine and benzimidazole substituents result in small, but potentially significant different physical and chemical properties.
Direct comparison of pantoprazole-sodium with other anti-secretory drugs showed that it was significantly more effective than H2-receptor antagonists and either equivalent or better than other clinically used PPIs. Another study states rabeprazole undergoes activation over a greater pH range than omeprazole, lansoprazole, and pantoprazole, and converts to the sulphenamide form more rapidly than any of these three drugs.
Most oral PPI preparations are enteric-coated, due to the rapid degradation of the drugs in the acidic conditions of the stomach. For example omeprazole is unstable in acid with a half-life of 2 min at pH 1-3, but is significantly more stable at pH 7 (half-life ca. 20 h).
The acid protective coating prevents conversion to the active principle in the lumen of the stomach, which then will react with any available sulfhydryl group in food and will not penetrate to the lumen of the secretory canaliculus
The oral bioavailability of PPIs is high; 77% for pantoprazole, 80-90% for lansoprazole and 89% for esomeprazole. All the PPIs except tenatoprazole are rapidly metabolized in the liver by CYP enzymes, mostly by CYP 2C19 and CYP 3A4. PPIs are sensitive to CYP enzymes and have different pharmacokinetic profiles. Studies comparing the efficacy of PPIs indicate that esomeprazole and tenatoprazole have stronger acid suppression, with a longer period of intragastric pH (pH > 4).
Studies of the effect of tenatoprazole on acid secretion in in vivo animal models, such as pylorus-ligated rats and acute gastric fistula rats, demonstrated a 2–4-fold more potent inhibitory activity compared with omeprazole. A more potent inhibitory activity was also shown in several models of induced gastric lesions. In Asian as well as Caucasian healthy subjects, tenatoprazole exhibited a sevenfold longer half-life than the existing H+,K+-ATPase inhibitors. It is thus hypothesized that a longer half-life results in a more prolonged inhibition of gastric acid secretion, especially during the night.
A strong relationship has been stated between the degree and duration of gastric acid inhibition, as measured by monitoring of the 24-h intragastric pH in pharmacodynamic studies, and the rate of healing and symptom relief reported.
A clinical study showed that nocturnal acid breakthrough duration was significantly shorter for 40 mg of tenatoprazole than for 40 mg of esomeprazole, with the conclusion that tenatoprazole was significantly more potent than esomeprazole during the night. Although, the therapeutic relevance of this pharmacological advantage deserves further study.
PPIs have been used successfully in triple-therapy regiments with clarithromycin and amoxicillin for the eradication of H.pylori with no significant difference between different PPI-based regimens.
P-CABs or APAs
Despite the fact that PPIs have revolutionized the treatment of GERDGerd
In Norse mythology, Gerðr is a jötunn, goddess, and the wife of the god Freyr. Gerðr is attested in the Poetic Edda, compiled in the 13th century from earlier traditional sources; the Prose Edda and Heimskringla, written in the 13th century by Snorri Sturluson; and in the poetry of skalds...
, there is still room for improvement in the speed of onset of acid suppression as well as mode of action that is independent of an acidic environment and also better inhibition of the proton pump. Therefore, a new class of PPIs, potassium-competitive acid blockers or acid pump antagonists, have been under development the past years and will most likely be the next generation of drugs that suppress gastric activity. These new agents can in a reversible and competitive fashion inhibit the final step in the gastric acid secretion with respect to K+ binding to the parietal cell gastric H+,K+-ATPase. That is, they block the action of the H+,K+-ATPase by binding to or near the site of the K+ channel. Since the binding is competitive and reversible these agents have the potential to achieve faster inhibition of acid secretion and longer duration of action compared to PPIs, resulting in quicker symptom relief and healing. The imidazopyridine based compound SCH28080 was the prototype of this class, and turned out to be hepatotoxic. Newer agents that are currently in development include CS-526, soraprazan and raveprazan in which the latter have reached clinical trials. Studies remain to determine whether these or other related compounds can become useful.
Other activity that PPIs may modulate is v-type H+-ATPase activity, which is widely distributed in a variety of cells in the human body. Among these, the acid-producing systems in osteoclasts and leukocytes are well developed for maintaining bone turnover and exhibit bactericidal roles and promote tissue-destructive inflammation. Hence, there is still much potential for research on the pharmacological and clinical aspects of PPI treatment.
See also
- DigestionDigestionDigestion is the mechanical and chemical breakdown of food into smaller components that are more easily absorbed into a blood stream, for instance. Digestion is a form of catabolism: a breakdown of large food molecules to smaller ones....
- StomachStomachThe stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
- Gastric acidGastric acidGastric acid is a digestive fluid, formed in the stomach. It has a pH of 1 to 2 and is composed of hydrochloric acid , and large quantities of potassium chloride and sodium chloride...
- Gastroesophageal reflux diseaseGastroesophageal reflux diseaseGastroesophageal reflux disease , gastro-oesophageal reflux disease , gastric reflux disease, or acid reflux disease is chronic symptoms or mucosal damage caused by stomach acid coming up from the stomach into the esophagus...
- Hydrogen potassium ATPaseHydrogen potassium ATPaseGastric hydrogen potassium ATPase is also known as H+/K+ ATPase- Function and location :The gastric hydrogen potassium ATPase or H+/K+ ATPase is the proton pump of the stomach and, as such, is the enzyme primarily responsible for the acidification of the stomach contents...
- Proton pump inhibitorProton pump inhibitorProton-pump inhibitors are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available today. The group followed and has largely superseded another group of pharmaceuticals with similar...
- Discovery and development of Bcr-Abl tyrosine kinase inhibitors