Discovery, synthesis, selectivity modulation and DMPK characterization of 5-azaspiro[2.4]heptanes as potent orexin receptor antagonists

作者：Stasi Luigi Piero^*; Artusi Roberto; Bovino Clara; Buzzi Benedetta; Canciani Luca; Caselli Gianfranco; Colace Fabrizio; Garofalo Paolo; Giambuzzi Silvia; Larger Patrice; Letari Ornella; Mandelli Stefano; Perugini Lorenzo; Pucci Sabrina; Salvi Matteo; Toro PierLuigi

来源：Bioorganic & Medicinal Chemistry Letters, 2013, 23(9): 2653-2658.

DOI：10.1016/j.bmcl.2013.02.093

• Orexin antagonists
• DORA
• 7TM
• DMPK
• TDI

Starting from a orexin 1 receptor selective antagonist 4,4-disubstituted piperidine series a novel potent 5-azaspiro[2.4]heptane dual orexin 1 and orexin 2 receptor antagonist class has been discovered. SAR and Pharmacokinetic optimization of this series is herein disclosed. Lead compound 15 exhibits potent activity against orexin 1 and orexin 2 receptors along with low cytochrome P450 inhibition potential, good brain penetration and oral bioavailability in rats.

• 出版日期2013-5-1