Discovery of MK-3697: A selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia

MK-1064 was recently disclosed as a selective orexin 2 receptor antagonist (2-SORA) possessing a profile commensurate with clinical investigation for the treatment of insomnia. Two issues arose during preclinical profiling of MK-1064: stability in low pH media and moderate TDI of CYP3A4. A mechanistic hypothesis for low pH hydrolysis initially drove compound design and optimization of A, B, and C rings of MK-1064 resulted in the amelioration of both issues and the discovery of MK-3697. 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. These studies resulted in the discovery of 2,5-disubstituted isonicotinamide 2-SORAs such as compound 24 that demonstrated improved stability and TDI profiles as well as excellent sleep efficacy across species.