Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold‐Hopping Approach

Abstract

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.

The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468

“…A 30 mg/kg dose increased non-REM, REM, and total sleep time in telemetrized rats and decreased the latency to the first episode of persistent non-REM and REM sleep compared with vehicle-treated animals. The pharmacological profiles in the rat were similar to each other and comparable to other DORAs described in literature (Aissaoui et al, 2008;Boss et al, 2008Boss et al, , 2014Cox et al, 2010;Sifferlen et al, 2010Sifferlen et al, , 2013Sifferlen et al, , 2015Winrow et al, 2012;Heidmann et al, 2016). No clear differentiation between compounds was therefore possible on the basis of drug efficacy in rats.…”

Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis, Structure–Activity Relationships, and Sleep‐Promoting Properties in Rats

“…[36] For our SAR studies, we kept the aryltriazolylcarboxamide and the unsubstituted phenyloxadiazole constant, and investigated the impact of replacing the piperidinec ore on potencya nd selectivity (Table 2). [36] For our SAR studies, we kept the aryltriazolylcarboxamide and the unsubstituted phenyloxadiazole constant, and investigated the impact of replacing the piperidinec ore on potencya nd selectivity (Table 2).…”

“…We turned our attention to modifyingt he core, as we knew from in-house data that core modifications can influence the selectivity profile of ac lass of compounds. [36] For our SAR studies, we kept the aryltriazolylcarboxamide and the unsubstituted phenyloxadiazole constant, and investigated the impact of replacing the piperidinec ore on potencya nd selectivity (Table 2). Ideally,t he core replacementw ould lead to compoundsw ith increased potency at OX 2 Ra nd therefore to compounds with aD ORA profile.…”

Optimisation of novel 4, 8-disubstituted dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119 agonists

“…The intermediates amine or bicyclic amines 3-6 could be purchased or synthesised according to the reported procedures [33][34][35][36] . Coupling reaction of 4,6-dichloro-5-methoxypyrimidine with 4amino-3-fluorobenzonitrile in DMF under basic condition afforded compound 7, followed by demethylation using BBr 3 solution in dichloromethane under reflux condition gave hydroxyl compound 8.…”