Selective 5-HT_2C receptor agonists: Design and synthesis of pyridazine-fused azepines

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• 作者：Martin P. Green^a ; Gordon McMurray^b ; R. Ian Storer^a ; ^{ian.storer@pfizer.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ADME ; absorption ; distribution ; metabolism ; and excretion ; CHO ; Chinese hamster ovary ; CNS ; central nervous system ; ER ; efflux ratio ; FLIPR ; fluorescence imaging plate reader ; HLM ; human liver microsomes ; MDCK ; Madin&ndash ; Darby Canine Kidney cell line ; MDR-1 ; multidrug resistance gene 1 ; P-gp ; P-glycoprotein transporter ; RRCK ; Ralph Russ Canine Kidney cell line ; SPA ; scintillation proximity assay ; TFA ; trifluoroacetic acid
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 August 2016
• 年：2016
• 卷：26
• 期：16
• 页码：4117-4121
• 全文大小：1285 K

文摘

Heterocycle-fused azepines are discussed as potent 5-HT_2C receptor agonists with excellent selectivity over 5-HT_2B agonism. Synthesis and structure activity relationships are outlined for a series of bicyclic pyridazino[3,4-d]azepines. By comparison with earlier published work, in vitro assays predict a high probability for achieving CNS penetration for a potent and selective compound 15a, a pre-requisite to achieve in vivo efficacy.