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JNJ-7925476

Identifiers
IUPAC name (6S,10bR)-6-(4-Ethynylphenyl)-1H,2H,3H,5H,6H,10bH-pyrrolo[2,1-a]isoquinoline
CAS Number	129540-12-1 Y HCl: 109085-56-5 Y
PubChemCID	13903191
ChemSpider	23130640
UNII	VSM44B5G3G HCl: IQ02SF57WP Y
ChEMBL	ChEMBL286312
CompTox Dashboard(EPA)	DTXSID001134549
Chemical and physical data
Formula	C20H19N
Molar mass	273.379 g·mol−1
3D model (JSmol)	Interactive image
SMILES C#CC1=CC=C(C=C1)[C@@H]2CN3CCC[C@@H]3C4=CC=CC=C24
InChI InChI=1S/C20H19N/c1-2-15-9-11-16(12-10-15)19-14-21-13-5-8-20(21)18-7-4-3-6-17(18)19/h1,3-4,6-7,9-12,19-20H,5,8,13-14H2/t19-,20+/m0/s1 Key:YPFCCQUUZJDQAM-VQTJNVASSA-N
(verify)

JNJ-7925476 is atriple reuptake inhibitorantidepressant discovered byJohnson & Johnson,^[1] but never marketed.

These molecules were first prepared byBruce E. Maryanoff and coworkers during the late 1970s–1980s.^[2][3][4] The structure is apyrroloisoquinoline core, with an overlaidbenzhydryl motif.

Incorporating thepyrrolidino ring onto thetetrahydroisoquinoline scaffolding markedly improves potency, although this only works for one of the availablestereoisomers. JNJ-7925476 is a racemic preparation of the more potentdiastereomer. Of these enantiomers, theeutomer is the (6R,10bS) stereoisomer, known as JNJ-39836966, and thedistomer, (6S,10bR), is JNJ-39836732

There is some confusion over the nomenclature andcis/trans isomeric relationship at the piperidine ring. The compounds as depicted have the carbon of the pyrrolidine carbon and the phenylcis, but Maryanoff and coworkers are of the opinion that the compound istrans.^[1] (see abstract)

The reason for this is not known because it was referred to as "cis" in earlier reports, and then later reassigned.

Ki values (nM) for JNJ-7925476 and its constituent enantiomers (JNJ-39836966 and JNJ-39836732)

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.

Elevations in extracellular DA in vivo was higher than expected on the basis of the in vitro transporter affinities.

The authors speculate that this could be because in the PFC where DATs are low in number, DA is predominantly transported via the NET.^[5]

• ~ 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 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 (cf. 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.

AK Dutta, et al. draws JNJ-7925476 with a fluorine in lieu of an ethynyl, without specifying the exact stereochemistry, e.g.^[6][7][8][9]

For JNJ-7925476 itself, the Ethynyl group is made from thep-iodo group (i.e.PC9951513), although no actual attempt was made by any of the authors to characterize this into the SAR list of quantitative data. LikeRTI-55 it was made prepared with radiolabelled iodine is an excellent way to scan the brain usingpositron emission tomography.

Aloke Dutta's compound can also be made in radiolabelled form, alaFlubatine.

Instead of alkyne, one can also replace the halogen with cyanide (nitrile), alacitalopram. Although not inputted into the tablet above, this was another one of the McNeal analogues.

Expanding the ring size frompyrrolidino topiperidinyl resulted in compounds that wereimpotent, although contracting the ring size from 5 → 4 did not have negative repercussions on the resultant potency.

TheN-acyliminium cyclization route; and themandelic acid andstyrene oxide route were employed for most of the target compounds.

The SS/RR diastereomers as the principle products if one follows the above steps.^[10][11]

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, atert-butyl or a cyclohexyl was used, then it was possible to alter the stereochemical discourse of the reaction.^[12]

Hydrogenation of an appropriately positioned olefin might be expected to work.^[14][15]

But the ketone cannot be reduced to an alcohol because it is part of anamide.

• Ethynyl compounds
• Serotonin–norepinephrine–dopamine reuptake inhibitors
• Stimulants
• Pyrroloisoquinolines
• Drugs developed by Johnson & Johnson
• Abandoned drugs

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