Wikipedia

JNJ-7925476

JNJ-7925476 is a triple reuptake inhibitor antidepressant discovered by Johnson & Johnson,[1] but never marketed.

JNJ-7925476
Identifiers
  • (6S,10bR)-6-(4-Ethynylphenyl)-1H,2H,3H,5H,6H,10bH-pyrrolo[2,1-a]isoquinoline
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC20H19N
Molar mass273.379 g·mol−1
3D model (JSmol)
  • C#CC1=CC=C(C=C1)[C@@H]2CN3CCC[C@@H]3C4=CC=CC=C24
  • 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)

These molecules were first prepared by Bruce E. Maryanoff and coworkers during the late 1970s–1980s.[2][3][4] The structure is a pyrroloisoquinoline core, with an overlaid benzhydryl motif.

Incorporating the pyrrolidino ring onto the tetrahydroisoquinoline scaffolding markedly improves potency, although this only works for one of the available stereoisomers. JNJ-7925476 is a racemic preparation of the more potent diastereomer. Of these enantiomers, the eutomer is the (6R,10bS) stereoisomer, known as JNJ-39836966, and the distomer, (6S,10bR), is JNJ-39836732

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

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

In-vitro characterization

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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 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

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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 (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

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3d structure, Y = OMe
 
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 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.

Para-Fluoro

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JNJ-7925476 according to AK Dutta

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 the p-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. Like RTI-55 it was made prepared with radiolabelled iodine is an excellent way to scan the brain using positron emission tomography.

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

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

Ring size structure activity relationships

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Expanding the ring size from pyrrolidino 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.

Chemistry

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The N-acyliminium cyclization route; and the mandelic acid and styrene oxide route were employed for most of the target compounds.

 
Pyrroloisoquinoline Synthesis

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

Stereoselective reaction

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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 an amide.

References

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  1. ^ a b Aluisio L, Lord B, Barbier AJ, Fraser IC, Wilson SJ, Boggs J, et al. (June 2008). "In-vitro and in-vivo characterization of JNJ-7925476, a novel triple monoamine uptake inhibitor". European Journal of Pharmacology. 587 (1–3): 141–6. doi:10.1016/j.ejphar.2008.04.008. PMID 18499098.
  2. ^ Maryanoff BE, McComsey DF, Castanzo MJ, Setler PE, Gardocki JF, Shank RP, Schneider CR (August 1984). "Pyrroloisoquinoline antidepressants. Potent, enantioselective inhibition of tetrabenazine-induced ptosis and neuronal uptake of norepinephrine, dopamine, and serotonin". Journal of Medicinal Chemistry. 27 (8): 943–6. doi:10.1021/jm00374a001. PMID 6747993.
  3. ^ Maryanoff BE, McComsey DF, Gardocki JF, Shank RP, Costanzo MJ, Nortey SO, et al. (August 1987). "Pyrroloisoquinoline antidepressants. 2. In-depth exploration of structure-activity relationships". Journal of Medicinal Chemistry. 30 (8): 1433–54. doi:10.1021/jm00391a028. PMID 3039136.
  4. ^ Maryanoff BE, Vaught JL, Shank RP, McComsey DF, Costanzo MJ, Nortey SO (October 1990). "Pyrroloisoquinoline antidepressants. 3. A focus on serotonin". Journal of Medicinal Chemistry. 33 (10): 2793–7. doi:10.1021/jm00172a018. PMID 2213832.
  5. ^ Morón JA, Brockington A, Wise RA, Rocha BA, Hope BT (January 2002). "Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines". The Journal of Neuroscience. 22 (2): 389–95. doi:10.1523/JNEUROSCI.22-02-00389.2002. PMC 6758674. PMID 11784783.
  6. ^ Dutta AK, Santra S, Sharma H, Voshavar C, Xu L, Mabrouk O, et al. (2014). "Pharmacological and behavioral characterization of D-473, an orally active triple reuptake inhibitor targeting dopamine, serotonin and norepinephrine transporters". PLOS ONE. 9 (11): e113420. Bibcode:2014PLoSO...9k3420D. doi:10.1371/journal.pone.0113420. PMC 4245125. PMID 25427177.
  7. ^ Santra S, Gogoi S, Gopishetty B, Antonio T, Zhen J, Reith ME, Dutta AK (December 2012). "Structural exploration of (3S,6S)-6-benzhydryl-N-benzyltetrahydro-2H-pyran-3-amine analogues: identification of potent triple monoamine reuptake inhibitors as potential antidepressants". ChemMedChem. 7 (12): 2093–100. doi:10.1002/cmdc.201200352. PMC 3733990. PMID 23060293.
  8. ^ Santra S, Sharma H, Vedachalam S, Antonio T, Reith M, Dutta A (February 2015). "Development of potent dopamine-norepinephrine uptake inhibitors (DNRIs) based on a (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol molecular template". Bioorganic & Medicinal Chemistry. 23 (4): 821–8. doi:10.1016/j.bmc.2014.12.040. PMC 4318756. PMID 25593099.
  9. ^ Gopishetty B, Hazeldine S, Santra S, Johnson M, Modi G, Ali S, et al. (April 2011). "Further structure-activity relationship studies on 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol: identification of compounds with triple uptake inhibitory activity as potential antidepressant agents". Journal of Medicinal Chemistry. 54 (8): 2924–32. doi:10.1021/jm200020a. PMC 3085959. PMID 21446715.
  10. ^ Maryanoff B (1979). "Iminium ion cyclizations. Highly stereoselective synthesis of substituted tetrahydroisoquinoline derivatives". Tetrahedron Letters. 20 (40): 3797–3800. doi:10.1016/S0040-4039(01)95527-3.
  11. ^ Maryanoff BE, Mccomsey DF, Duhl-Emswiler BA (1983). "Stereochemistry of intramolecular amidoalkylation reactions in the synthesis of polycyclic isoquinoline derivatives". The Journal of Organic Chemistry. 48 (25): 5062–5074. doi:10.1021/jo00173a053.
  12. ^ Maryanoff BE, Mccomsey DF, Almond HR, Mutter MS, Bemis GW, Whittle RR, Olofson RA (1986). "Dramatic reversal of diastereoselectivity in an N-acyliminium ion cyclization leading to hexahydropyrrolo[2,1-a]isoquinolines. A case of competing steric interactions". The Journal of Organic Chemistry. 51 (8): 1341–1346. doi:10.1021/jo00358a034.
  13. ^ U.S. patent 4,837,328
  14. ^ Maryanoff BE, McComsey DF, Mutter MS, Sorgi KL, Maryanuff CA (1988). "Highly stereocontrolled proton transfer in an enammonium-iminium rearrangement. Mechanism of the stereoselective deoxygenation of 6-aryl-6-hydroxy-1,2,3,5,6,10b-hexahydropyrrolo[2.1-]isoquinolines with borane-thf in trifluoroacetic acid". Tetrahedron Letters. 29 (40): 5073–5076. doi:10.1016/S0040-4039(00)80682-6.
  15. ^ McComsey DF, Maryanoff BE (August 2000). "3-Aza-cope rearrangement of quaternary N-allyl enammonium salts. Stereospecific 1,3 allyl migration from nitrogen to carbon on a tricyclic template". The Journal of Organic Chemistry. 65 (16): 4938–43. doi:10.1021/jo000363h. PMID 10956475.
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