Brasofensine
Encyclopedia
Brasofensine is a phenyltropane
that had been under development for the treatment of Parkinson's
and Alzheimer's disease
. Phase II trials were conducted in 1996 and brasofensine was shown to be both effective and well tolerated at a dose of 4 mg, however development was stopped after in vivo cis-anti isomerization of the 2α-methyloxime group was reported. In animal models of Parkinson's disease, brasofensine was effective in stimulating LMA and reversing akinesia.
The isomerization of brasofensine is not between the alpha and beta positions on the 2 position of the tropane ring but rather the E/Z isomerization of the imine
(i.e. "methyl-aldoxime"). It was believed that this process occurs in vivo although it cannot be ruled out as a possibility that some isomerization also occurs prior to ingestion.
The (Z)-isomer has been consigned the name BMS-205912
The inversion barrier
for a methylaldoxime may or may not be measurable. The relative ratio of E/Z should lie in an equilibrium and this needs to be measured. It is not unreasonable to anticipate that this distribution can be influenced by complexation with various solvents under an appropriate choice of reaction temperature. This possibility should be considered. The inversion barrier for isomerization of a methylaldoxime -in brasofensine in particular- must be calculated so it is known how easily the isomeric forms are interconverted.
In PD, symptoms do not begin to manifest until there has been an 80% reduction in dopaminergic neurons, particularly in the substantia nigra
brain region. Subsequently there is decreased dopaminergic neurotransmission, resulting in movement disorders, slurred speech, and the like. The object of a dopamine reuptake inhibitor
is to "make the best out of" the dopamine that is still available. Additionally, a DRI can be expected to enhance the effectiveness of exogenously delivered dopamine, in the form of L-DOPA.
) was also much greater than for humans, who excrete more of the product intact. For humans, most (~90%) of the 14C
was detected in the urine
, whereas for rats as much as 80% of the 14C was in their feces.
It is well-known that a Schiff base
is more stable than a regular imine. Imine formation is a reversible process, and in the study by Zhu et al., none of the aldehyde was recovered/detected by GC-MS. Instead, the breakdown products were N-demethyl metabolites.
The ester was first reduced to the alcohol, then oxidized to the aldehyde, followed by condensation with methoxyamine. Methods have been reported for the direct reduction of esters to aldehydes, however in practice there has been some difficulty in effecting this transformation. 17-20
In particular, the fragility of the aldehyde meant that it collapsed to the alcohol and was not isolable even though a wide assortment of reducing agents and reactions conditions were attempted.
Following this, Swern oxidation
was employed to obtain the corresponding aldehyde.
Phenyltropane
Phenyltropanes were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, they are not the only researchers that have prepared these...
that had been under development for the treatment of Parkinson's
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
and Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
. Phase II trials were conducted in 1996 and brasofensine was shown to be both effective and well tolerated at a dose of 4 mg, however development was stopped after in vivo cis-anti isomerization of the 2α-methyloxime group was reported. In animal models of Parkinson's disease, brasofensine was effective in stimulating LMA and reversing akinesia.
The isomerization of brasofensine is not between the alpha and beta positions on the 2 position of the tropane ring but rather the E/Z isomerization of the imine
Imine
An imine is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom or an organic group. If this group is not a hydrogen atom, then the compound is known as a Schiff base...
(i.e. "methyl-aldoxime"). It was believed that this process occurs in vivo although it cannot be ruled out as a possibility that some isomerization also occurs prior to ingestion.
The (Z)-isomer has been consigned the name BMS-205912
The inversion barrier
Inversion barrier
In molecular geometry, the term inversion barrier refers to the amount of energy required for the geometric structure of a molecule to undergo the conformational change of inversion; i.e. for the molecule to be turned inside out. Nitrogen inversion is one example of such a transition in the...
for a methylaldoxime may or may not be measurable. The relative ratio of E/Z should lie in an equilibrium and this needs to be measured. It is not unreasonable to anticipate that this distribution can be influenced by complexation with various solvents under an appropriate choice of reaction temperature. This possibility should be considered. The inversion barrier for isomerization of a methylaldoxime -in brasofensine in particular- must be calculated so it is known how easily the isomeric forms are interconverted.
In PD, symptoms do not begin to manifest until there has been an 80% reduction in dopaminergic neurons, particularly in the substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
brain region. Subsequently there is decreased dopaminergic neurotransmission, resulting in movement disorders, slurred speech, and the like. The object of a dopamine reuptake inhibitor
Dopamine reuptake inhibitor
A dopamine reuptake inhibitor is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter...
is to "make the best out of" the dopamine that is still available. Additionally, a DRI can be expected to enhance the effectiveness of exogenously delivered dopamine, in the form of L-DOPA.
Metabolism and Distribution
NS-2214 is not particularly stable and is readily metabolized. 50 mg was the dosage that was tried on humans, although the starting dose was 2 mg. Interestingly, because rats metabolism is much greater than humans, the amount of metabolites detected in their urine (and fecesFeces
Feces, faeces, or fæces is a waste product from an animal's digestive tract expelled through the anus or cloaca during defecation.-Etymology:...
) was also much greater than for humans, who excrete more of the product intact. For humans, most (~90%) of the 14C
Carbon-14
Carbon-14, 14C, or radiocarbon, is a radioactive isotope of carbon with a nucleus containing 6 protons and 8 neutrons. Its presence in organic materials is the basis of the radiocarbon dating method pioneered by Willard Libby and colleagues , to date archaeological, geological, and hydrogeological...
was detected in the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
, whereas for rats as much as 80% of the 14C was in their feces.
It is well-known that a Schiff base
Schiff base
A Schiff base, named after Hugo Schiff, is a compound with a functional group that contains a carbon-nitrogen double bond with the nitrogen atom connected to an aryl or alkyl group, not hydrogen....
is more stable than a regular imine. Imine formation is a reversible process, and in the study by Zhu et al., none of the aldehyde was recovered/detected by GC-MS. Instead, the breakdown products were N-demethyl metabolites.
Chemistry
In particular, the fragility of the aldehyde meant that it collapsed to the alcohol and was not isolable even though a wide assortment of reducing agents and reactions conditions were attempted.
Following this, Swern oxidation
Swern oxidation
The Swern oxidation, named after Daniel Swern, is a chemical reaction whereby a primary or secondary alcohol is oxidized to an aldehyde or ketone using oxalyl chloride, dimethyl sulfoxide and an organic base, such as triethylamine...
was employed to obtain the corresponding aldehyde.