Anthony J Roecker, Thomas S Reger, M Christa Mattern, Swati P Mercer, Jeffrey M Bergman, John D Schreier, Rowena V Cube, Christopher D Cox, Dansu Li, Wei Lemaire, Joseph G Bruno, C Meacham Harrell, Susan L Garson, Anthony L Gotter, Steven V Fox, Joanne Stevens, Pamela L Tannenbaum, Thomayant Prueksaritanont, Tamara D Cabalu, Donghui Cui, Joyce Stellabott, George D Hartman, Steven D Young, Christopher J Winrow, John J Renger, Paul J Coleman
Orexin receptor antagonists have demonstrated clinical utility for the treatment of insomnia. The majority of clinical efforts to date have focused on the development of dual orexin receptor antagonists (DORAs), small molecules that antagonize both the orexin 1 and orexin 2 receptors. Our group has recently disclosed medicinal chemistry efforts to identify highly potent, orally bioavailable selective orexin 2 receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the 'triaryl' amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4...
October 15, 2014: Bioorganic & Medicinal Chemistry Letters