Ocinaplon

Ocinaplon is an anxiolytic drug in the pyrazolopyrimidine family of drugs. Other pyrazolopyrimidine drugs include zaleplon and indiplon.

Ocinaplon

Clinical data
ATC code	none
Identifiers
IUPAC name pyridin-2-yl-(7-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-3-yl)methanone
CAS Number	96604-21-6
PubChem CID	216456
IUPHAR/BPS	4277
ChemSpider	187602
UNII	2H6KVC5E76
KEGG	D02617
CompTox Dashboard (EPA)	DTXSID00242362
Chemical and physical data
Formula	C17H11N5O
Molar mass	301.309 g·mol^−1
3D model (JSmol)	Interactive image
SMILES O=C(c1cnn2c(ccnc12)c3ccncc3)c4ncccc4
InChI InChI=1S/C17H11N5O/c23-16(14-3-1-2-7-19-14)13-11-21-22-15(6-10-20-17(13)22)12-4-8-18-9-5-12/h1-11H Key:OQJFBUOFGHPMSR-UHFFFAOYSA-N
(verify)

Ocinaplon has a similar pharmacological profile to the benzodiazepine family of drugs, but with mainly anxiolytic properties and relatively little sedative or amnestic effect.[1]

Medical uses

A 2019 review found tentative evidence of benefit in anxiety.[2]

Mechanism of action

The mechanism of action by which ocinaplon produces its anxiolytic effects is by modulating GABA_A receptors,[3] although ocinaplon is more subtype-selective than most benzodiazepines.[4]

Availability

Development of ocinaplon is discontinued due to liver complications that occurred in one of the Phase III subjects.[5]

Synthesis

Ocinaplon synthesis: U.S. Patent 4,521,422 Further reading:[6][7]

Condensation of 4-Acetylpyridine[8] with N,N-Dimethylformamide dimethyl acetal (DMFDMA) gives the "enamide" (3). This is then condensed with (3-Amino-1H-pyrazol-4-yl)(2-pyridinyl)methanone (4) (96219-90-8).[9][10] This is the same intermediate as was used in the synthesis of zaleplon in which the nitrile is replaced by a 2-acetylpyridil moiety. This affords the anxiolytic agent ocinaplon (5).

References

1. Lippa A, Czobor P, Stark J, Beer B, Kostakis E, Gravielle M, et al. (May 2005). "Selective anxiolysis produced by ocinaplon, a GABA(A) receptor modulator". Proceedings of the National Academy of Sciences of the United States of America. 102 (20): 7380–5. Bibcode:2005PNAS..102.7380L. doi:10.1073/pnas.0502579102. PMC 1129138. PMID 15870187.
2. Slee A, Nazareth I, Bondaronek P, Liu Y, Cheng Z, Freemantle N (February 2019). "Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis". Lancet. 393 (10173): 768–777. doi:10.1016/S0140-6736(18)31793-8. PMID 30712879. S2CID 72332967.
3. Mirza NR, Rodgers RJ, Mathiasen LS (March 2006). "Comparative cue generalization profiles of L-838, 417, SL651498, zolpidem, CL218,872, ocinaplon, bretazenil, zopiclone, and various benzodiazepines in chlordiazepoxide and zolpidem drug discrimination". The Journal of Pharmacology and Experimental Therapeutics. 316 (3): 1291–9. doi:10.1124/jpet.105.094003. PMID 16339395. S2CID 21913400.
4. Atack JR (May 2005). "The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics". Expert Opinion on Investigational Drugs. 14 (5): 601–18. doi:10.1517/13543784.14.5.601. PMID 15926867. S2CID 22793644.
5. "DOV Pharmaceutical, Inc. Places Ocinaplon Phase III Clinical Trial On Hold". PR NewsWire. Archived from the original on 4 March 2016.
6. Baumann M, Baxendale IR (October 2013). "An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles". Beilstein Journal of Organic Chemistry. 9: 2265–319. doi:10.3762/bjoc.9.265. PMC 3817479. PMID 24204439.
7. ARKIVOC 2010 (ii) 267-282
8. LaMattina JL, Sulesk RT (1986). "A-Amino Acetals: 2,2-Diethoxy-2-(4-Pyridyl)Ethylamine". Organic Syntheses. 64: 19. doi:10.15227/orgsyn.064.0019.
9. U.S. Patent 4,900,836
10. CA 1243029