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
Chemistry Department, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.
Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Groton Laboratories , Eastern Point Road, Groton, Connecticut 06340, United States.
ACS Med Chem Lett. 2015 Jan 20;6(3):329-33. doi: 10.1021/ml500507v. eCollection 2015 Mar 12.
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.
公开了一系列强效且选择性的5-HT2C受体激动剂吡啶并[3,4-d]氮杂卓。化合物7（PF-04781340）被确定为合适的先导化合物，因为它具有良好的5-HT2C活性、对5-HT2B激动作用的选择性以及与口服可用和中枢神经系统渗透特性相称的体外吸收、分布、代谢和排泄（ADME）性质。概述了一种新型双环四取代吡啶核心模板的合成，包括对由氨级联环化导致意外形成氨基吡啶13的原因的解释。
