Ocinaplon Explained

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

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 GABAA 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

Condensation of 4-Acetylpyridine[6] 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).[7] 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).

Notes and References

  1. Lippa A, Czobor P, Stark J, Beer B, Kostakis E, Gravielle M, Bandyopadhyay S, Russek SJ, Gibbs TT, Farb DH, Skolnick P . 6 . 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 . May 2005 . 15870187 . 1129138 . 10.1073/pnas.0502579102 . 2005PNAS..102.7380L . free .
  2. Slee A, Nazareth I, Bondaronek P, Liu Y, Cheng Z, Freemantle N . Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis . Lancet . 393 . 10173 . 768–777 . February 2019 . 30712879 . 10.1016/S0140-6736(18)31793-8 . 72332967 .
  3. Mirza NR, Rodgers RJ, Mathiasen LS . 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 . March 2006 . 16339395 . 10.1124/jpet.105.094003 . 21913400 .
  4. Atack JR . 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 . May 2005 . 15926867 . 10.1517/13543784.14.5.601 . 22793644 .
  5. Web site: DOV Pharmaceutical, Inc. Places Ocinaplon Phase III Clinical Trial On Hold . https://web.archive.org/web/20160304042155/http://www.prnewswire.com/news-releases/dov-pharmaceutical-inc-places-ocinaplon-phase-iii-clinical-trial-on-hold-55011422.html . 4 March 2016 . PR NewsWire .
  6. LaMattina JL, Sulesk RT . 10.15227/orgsyn.064.0019. A-Amino Acetals: 2,2-Diethoxy-2-(4-Pyridyl)Ethylamine. Organic Syntheses. 64. 19. 1986.
  7. CA. 1243029.

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