1384064-38-3Relevant academic research and scientific papers
Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold-Hopping Approach
Heidmann, Bibia,Gatfield, John,Roch, Catherine,Treiber, Alexander,Tortoioli, Simone,Brotschi, Christine,Williams, Jodi T.,Bolli, Martin H.,Abele, Stefan,Sifferlen, Thierry,Jenck, Fran?ois,Boss, Christoph
, p. 2132 - 2146 (2016)
Starting from suvorexant (trade name Belsomra), we successfully identified interesting templates leading to potent dual orexin receptor antagonists (DORAs) via a scaffold-hopping approach. Structure–activity relationship optimization allowed us not only to improve the antagonistic potency on both orexin 1 and orexin 2 receptors (Ox1 and Ox2, respectively), but also to increase metabolic stability in human liver microsomes (HLM), decrease time-dependent inhibition of cytochrome P450 (CYP) 3A4, and decrease P-glycoprotein (Pgp)-mediated efflux. Compound 80 c [{(1S,6R)-3-(6,7-difluoroquinoxalin-2-yl)-3,8-diazabicyclo[4.2.0]octan-8-yl}(4-methyl-[1,1′-biphenyl]-2-yl)methanone] is a potent and selective DORA that inhibits the stimulating effects of orexin peptides OXA and OXB at both Ox1 and Ox2. In calcium-release assays, 80 c was found to exhibit an insurmountable antagonistic profile at both Ox1 and Ox2, while displaying a sleep-promoting effect in rat and dog models, similar to that of the benchmark compound suvorexant.
3,8-DIAZA-BICYCLO[4.2.0]OCT-3-YL AMIDES
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Page/Page column 90, (2012/07/13)
The present invention relates to 3,8-diaza-bicyclo[4.2.0]oct-3-yl amide derivatives of formula (I), wherein the relative configuration of the diazabicyclooctane moiety is cis; and wherein Ar1, and Ar2 are as described in the description, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as orexin receptor antagonists.
