| Literature DB >> 25248679 |
Anthony J Roecker1, Thomas S Reger2, M Christa Mattern3, Swati P Mercer3, Jeffrey M Bergman3, John D Schreier3, Rowena V Cube3, Christopher D Cox3, Dansu Li3, Wei Lemaire4, Joseph G Bruno4, C Meacham Harrell5, Susan L Garson5, Anthony L Gotter5, Steven V Fox6, Joanne Stevens6, Pamela L Tannenbaum6, Thomayant Prueksaritanont7, Tamara D Cabalu7, Donghui Cui7, Joyce Stellabott8, George D Hartman3, Steven D Young3, Christopher J Winrow5, John J Renger5, Paul J Coleman3.
Abstract
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.Entities:
Keywords: 2-SORA; Antagonists; Insomnia; Neurotransmitters; Orexin receptors
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Year: 2014 PMID： 25248679 DOI： 10.1016/j.bmcl.2014.08.041
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823