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

作者：Rouquet Guy; Moore Dianna E; Spain Malcolm; Allwood Daniel M; Battilocchio Claudio; Blakemore David C; Fish Paul V; Jenkinson Stephen; Jessiman Alan S; Ley Steven V; McMurray Gordon; Storer R Ian^*

来源：ACS Medicinal Chemistry Letters, 2015, 6(3): 329-333.

DOI：10.1021/ml500507v

• Tetrasubstituted pyridines
• pyrido[3,4-d]azepine
• S-HT2C receptor agonist
• CNS penetration

A series of pyrido[3,4-diazepines that are potent and selective S-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.

• 出版日期2015-3