JNJ-7925476
Encyclopedia
JNJ-7925476 is a TRI antidepressant
currently under development by Johnson & Johnson
.
These molecules were first prepared by Bruce E. Maryanoff
, et al. during the late 1970s – 1980's. and is known as a pyrroloisoquinoline
, that is benzhydryl-containing.
Incorporating the pyrrolidino
ring onto the THIQ
scaffolding markedly improves potency, although this only works for one of the available diastereo/enantiomers. JNJ-7925476 is a racemic preparation of the more potent diastereomer
. The eutomer
, JNJ-39836966 has (6R,10bS)-stereochemistry
whereas the distomer
JNJ-39836732 will have (6S,10bR)-stereochemistry.
The compounds depicted appear to be cis but Maryanoff and coworkers are of the opinion that it is trans. (see abstract)
The reason for this is not known because it was referred to as "cis" to begin with, only reassigning it later.
Cyclohexane conformation
In vitro, JNJ-7925476 is ~18-fold selective for the hSERT (0.9 nM) over the hNET (16.6 nM).
Ex vivo
transporter occupancy of JNJ-7925476 (in rat brain) followed the ordering priority: NET > SERT > DAT.
This is consistent with the results cited earlier for rat brains (see SAR table dated 1987).
However, there is relatively poor correlation between the in vitro data presented for rats brains vs what was reported at the human transporters.
The authors reckon that this could be because in the PFC where DATs are low in number, DA is preferentially transported via the NET.
Ex vivo
occupancy of the DAT was much lower (<50%) at this dose though, whereas the NET and SERT were similar (~90%).
It took a much higher dose (c.f. 10 mg/kg) for the DAT occupancy to approach the same as the NET and SERT (i.e. saturation).
At saturation, the elevation in synaptic DA was extremely prolific (15 × baseline), whereas SER and NE was ≈ ½ this amount (i.e. 750%).
This is a collection of all of the analogs that had favorable biological activity or an interesting substitution pattern.
All compounds are racemic preparations with the exception that brackets are for pure (+) enantiomer.
to piperidinyl
resulted in compounds that were impotent, although contracting the ring size from 5 → 4 did not have negative repercussions on the resultant potency.
and styrene oxide
route were employed for most of the target compounds.
The SS/RR diastereomers as the principle products if one follows the above steps.
It is possible to epimerize the product to the desired RS/SR diastereomers, but the equilibrium is only 50/50.
Hence, alternative synthetic methods needed to be sought to obtain the desired isomer/s in diastereochemical excess.
If instead of an "aryl" group, a tert-butyl or a cyclohexyl was used, then it was possible to alter the stereochemical discourse of the reaction.
But the ketone cannot be reduced to an alcohol because it is part of an amide
.
2,2-diphenylethylamine
2-Phenylpyrrolidine
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
currently under development by Johnson & Johnson
Johnson & Johnson
Johnson & Johnson is an American multinational pharmaceutical, medical devices and consumer packaged goods manufacturer founded in 1886. Its common stock is a component of the Dow Jones Industrial Average and the company is listed among the Fortune 500....
.
These molecules were first prepared by Bruce E. Maryanoff
Bruce E. Maryanoff
Bruce Eliot Maryanoff is an American medicinal and organic chemist.-Background and contributions:...
, et al. during the late 1970s – 1980's. and is known as a pyrroloisoquinoline
Isoquinoline
Isoquinoline is a heterocyclic aromatic organic compound. It is a structural isomer of quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. In a broader sense, the term isoquinoline is used to make reference to isoquinoline...
, that is benzhydryl-containing.
Incorporating the pyrrolidino
Pyrrolidine
Pyrrolidine, also known as tetrahydropyrrole, is an organic compound with the molecular formula C4H9N. It is a cyclic secondary amine with a five-membered heterocycle containing four carbon atoms and one nitrogen atom...
ring onto the THIQ
Tetrahydroisoquinoline
Tetrahydroisoquinoline is a secondary amine with the chemical formula C9H11N.-Reactions:Like other secondary amines, tetrahydroisoquinoline can be oxidized to the corresponding nitrone using hydrogen peroxide, catalyzed by selenium dioxide....
scaffolding markedly improves potency, although this only works for one of the available diastereo/enantiomers. JNJ-7925476 is a racemic preparation of the more potent diastereomer
Diastereomer
Diastereomers are stereoisomers that are not enantiomers.Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more of the equivalent stereocenters and are not mirror images of each other.When two diastereoisomers differ from each other at...
. The eutomer
Eutomer
The eutomer is the molecular chiral enantiomer having the desired bioactivity, e. g. as as an active ingredient in a drug. On the other hand the enantiomer of the eutomer having the undesired bioactivity is called distomer....
, JNJ-39836966 has (6R,10bS)-stereochemistry
Stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
whereas the distomer
Distomer
The distomer is an enantiomer in an optically active compound. It is often the case that only a single one of the enantiomers contains all of the wanted bioactivity, the distomer is often less active, has no disired activity or may even be toxic....
JNJ-39836732 will have (6S,10bR)-stereochemistry.
The compounds depicted appear to be cis but Maryanoff and coworkers are of the opinion that it is trans. (see abstract)
The reason for this is not known because it was referred to as "cis" to begin with, only reassigning it later.
Cyclohexane conformation
Cyclohexane conformation
A cyclohexane conformation is any of several three-dimensional shapes that a cyclohexane molecule can assume while maintaining the integrity of its chemical bonds....
In-vitro characterization
Ki values (nM) for JNJ-7925476 and its constituent enantiomers (JNJ-39836966 and JNJ-39836732)| JNJ | rSERT | hSERT | hDAT | hNET |
|---|---|---|---|---|
| 7925476 | 0.4 | 0.9 | 5.2 | 16.6 |
| 39836966 | 0.33 | 0.27 | 1.6 | 15.8 |
| 39836732 | 17.0 | 4.1 | 74.3 | 227 |
In vitro, JNJ-7925476 is ~18-fold selective for the hSERT (0.9 nM) over the hNET (16.6 nM).
Ex vivo
Ex vivo
Ex vivo means that which takes place outside an organism. In science, ex vivo refers to experimentation or measurements done in or on tissue in an artificial environment outside the organism with the minimum alteration of natural conditions...
transporter occupancy of JNJ-7925476 (in rat brain) followed the ordering priority: NET > SERT > DAT.
This is consistent with the results cited earlier for rat brains (see SAR table dated 1987).
However, there is relatively poor correlation between the in vitro data presented for rats brains vs what was reported at the human transporters.
μ-Dialysis
Elevations in extracellular DA in vivo was higher than expected on the basis of the in vitro transporter affinities.The authors reckon that this could be because in the PFC where DATs are low in number, DA is preferentially transported via the NET.
- ~ 1 mg/kg of JNJ-7925476 caused concentrations of NE, 5-HT and DA to all be elevated by just under 500%, respectively.
Ex vivo
Ex vivo
Ex vivo means that which takes place outside an organism. In science, ex vivo refers to experimentation or measurements done in or on tissue in an artificial environment outside the organism with the minimum alteration of natural conditions...
occupancy of the DAT was much lower (<50%) at this dose though, whereas the NET and SERT were similar (~90%).
It took a much higher dose (c.f. 10 mg/kg) for the DAT occupancy to approach the same as the NET and SERT (i.e. saturation).
At saturation, the elevation in synaptic DA was extremely prolific (15 × baseline), whereas SER and NE was ≈ ½ this amount (i.e. 750%).
Pyrroloisoquinolines structure activity relationships
| X | Y | V | W | MA (mg/kg) | ptosis (mg/kg) | DA (nM) | NE (nM) | 5-HT (nM) |
| H | H | H | H | 0.34 (0.59) | 0.07 (0.05) | 11.3 (4.4) | 0.60 (0.37) | 23.5 (12.4) |
| H | H | OMe | OMe | 15.1 | 3.8 | 15.0 | 53.7 | 1540 |
| H | H | OH | OH | 0.87 | 0.53 | 43.5 | 10.5 | 124 |
| OMe | H | H | H | 0.27 | 0.03 | 5.2 | 0.79 | 1.7 |
| OH | H | H | H | 0.40 | 0.09 | 5.1 | 0.74 | 3.2 |
| H | OMe | H | H | ~0.2 | 0.07 | 15.8 | 0.65 | 7.2 |
| H | OH | H | H | >10 | 0.11 | 10.1 | 0.85 | 24.6 |
| H | H | H | OMe | no data | no data | 2.8 | 2.2 | 4.5 |
| OMe | OMe | H | H | 2.0 | 0.13 | 71.9 | 3.4 | 18.1 |
| OH | OH | H | H | 0.19 | 0.11 | 10.1 | 0.81 | 33.1 |
| Cl | H | H | H | 0.55 | 0.34 | 1.7 | 0.16 | 1.5 |
| H | Cl | H | H | ~0.1 | <0.1 | 2.5 | 0.45 | 7.3 |
| Cl | H | H | Cl | 37.4 | ~4 | 3.2 | 3.2 | 2.9 |
| Cl | Cl | H | H | 0.39 | 0.14 | 0.99 | 0.68 | 1.8 |
| F | H | H | H | ~0.2 | ~0.2 | 8.4 | 1.4 | 8.5 |
| F | H | H | F | >30 | 0.05 | 7.7 | 0.55 | 4.4 |
| NH2 | H | H | H | ~0.2 | ~0.01 | 0.86 | 0.20 | 44 |
| SMe | H | H | H | >30 (no data) | 0.30 (no data) | 41.2 (23.5) | 3.0 (1.8) | 0.62 (0.39) |
| Ethynyl | H | H | H | ~0.5 | ~0.5 | 2.6 | 0.94 | 1.0 |
| diclofensine | 10.9 | 8.8 | 10.3 | |||||
| WIN-25978 Amfonelic acid Amfonelic acid is a psychoactive drug and research chemical used in scientific studies. It was discovered while researchers were investigating novel antibiotics. It acts as a potent and highly selective dopamine reuptake inhibitor . It has a moderately long half-life of approximately 12 hours... |
7.2 | 41.1 | 879 | |||||
This is a collection of all of the analogs that had favorable biological activity or an interesting substitution pattern.
All compounds are racemic preparations with the exception that brackets are for pure (+) enantiomer.
Ring size structure activity relationships
Expanding the ring size from pyrrolidinoPyrrolidine
Pyrrolidine, also known as tetrahydropyrrole, is an organic compound with the molecular formula C4H9N. It is a cyclic secondary amine with a five-membered heterocycle containing four carbon atoms and one nitrogen atom...
to piperidinyl
Piperidine
Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...
resulted in compounds that were impotent, although contracting the ring size from 5 → 4 did not have negative repercussions on the resultant potency.
Chemistry
The N-acyliminium cyclization route; and the mandelic acidMandelic acid
Mandelic acid is an aromatic alpha hydroxy acid with the molecular formula C6H5CHCO2H. It is a white crystalline solid that is soluble in water and polar organic solvents. It is a useful precursor to various drugs...
and styrene oxide
Styrene oxide
Styrene oxide is an epoxide derived from styrene. It may be prepared by epoxidation of styrene with peroxybenzoic acid, in the Prilezhaev reaction:- Toxicology :...
route were employed for most of the target compounds.
The SS/RR diastereomers as the principle products if one follows the above steps.
It is possible to epimerize the product to the desired RS/SR diastereomers, but the equilibrium is only 50/50.
Hence, alternative synthetic methods needed to be sought to obtain the desired isomer/s in diastereochemical excess.
If instead of an "aryl" group, a tert-butyl or a cyclohexyl was used, then it was possible to alter the stereochemical discourse of the reaction.
Stereoselective reaction
Hydrogenation of an appropriately positioned olefin might be expected to work.But the ketone cannot be reduced to an alcohol because it is part of an amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
.
2,2-diphenylethylamine
2-Phenylpyrrolidine