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Design, Synthesis, and Evaluation of Tetrasubstituted Pyridines as Potent 5-HT2C Receptor Agonists.

ABSTRACT: A series of pyrido[3,4-d]azepines that are potent and selective 5-HT2C receptor agonists is disclosed. Compound 7 (PF-04781340) is identified as a suitable lead owing to good 5-HT2C potency, selectivity over 5-HT2B agonism, and in vitro ADME properties commensurate with an orally available and CNS penetrant profile. The synthesis of a novel bicyclic tetrasubstituted pyridine core template is outlined, including rationale to account for the unexpected formation of aminopyridine 13 resulting from an ammonia cascade cyclization.

SUBMITTER: Rouquet G

PROVIDER: S-EPMC4360148 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Design, Synthesis, and Evaluation of Tetrasubstituted Pyridines as Potent 5-HT2C Receptor Agonists.

Rouquet Guy G Moore Dianna E DE Spain Malcolm M Allwood Daniel M DM Battilocchio Claudio C Blakemore David C DC Fish Paul V PV Jenkinson Stephen S Jessiman Alan S AS Ley Steven V SV McMurray Gordon G Storer R Ian RI

ACS medicinal chemistry letters 20150120 3

A series of pyrido[3,4-d]azepines that are potent and selective 5-HT2C receptor agonists is disclosed. Compound 7 (PF-04781340) is identified as a suitable lead owing to good 5-HT2C potency, selectivity over 5-HT2B agonism, and in vitro ADME properties commensurate with an orally available and CNS penetrant profile. The synthesis of a novel bicyclic tetrasubstituted pyridine core template is outlined, including rationale to account for the unexpected formation of aminopyridine 13 resulting from ...[more]

PMID: 25815155

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