Discovery of ORN0829, a potent dual orexin 1/2 receptor antagonist for the treatment of insomnia |
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| Affiliation: | 1. Discovery Research Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan;2. Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan;1. Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA;2. Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Biotechnology Center, San Diego, CA 92121, USA;1. Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States;2. Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States;3. Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, United States;4. In Vivo Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States;5. In Vitro Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States;1. Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA;2. Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA;3. Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA;4. Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA |
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| Abstract: | Here, we present the design, synthesis, and SAR of dual orexin 1 and 2 receptor antagonists, which were optimized by balancing the antagonistic activity for orexin receptors and lipophilicity. Based on the prototype compound 1, ring construction and the insertion of an additional heteroatom into the resulting ring led to the discovery of orexin 1 and 2 receptor antagonists, which were 3-benzoyl-1,3-oxazinane derivatives. Within these derivatives, (−)-3h enabled a high dual orexin receptor antagonistic activity and a low lipophilicity. Compound (−)-3h exhibited potent sleep-promoting effects at a po dose of 1 mg/kg in a rat polysomnogram study, and optimal PK properties with a rapid Tmax and short half-lives in rats and dogs were observed, indicating a predicted human half-life of 0.9–2.0 h. Thus, (−)-3h (ORN0829; investigation code name, TS-142) was selected as a viable candidate and is currently in clinical development for the treatment of insomnia. |
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| Keywords: | Dual orexin receptor antagonist DORA Insomnia orexin 1 receptor orexin 2 receptor DORA" },{" #name" :" keyword" ," $" :{" id" :" k0045" }," $$" :[{" #name" :" text" ," _" :" dual orexin receptor antagonist SORA" },{" #name" :" keyword" ," $" :{" id" :" k0055" }," $$" :[{" #name" :" text" ," _" :" selective orexin receptor antagonist PSG" },{" #name" :" keyword" ," $" :{" id" :" k0065" }," $$" :[{" #name" :" text" ," _" :" polysomnography SAR" },{" #name" :" keyword" ," $" :{" id" :" k0075" }," $$" :[{" #name" :" text" ," _" :" structure-activity relationship Cbz" },{" #name" :" keyword" ," $" :{" id" :" k0085" }," $$" :[{" #name" :" text" ," _" :" benzyloxycarbonyl Boc" },{" #name" :" keyword" ," $" :{" id" :" k0095" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" italic" ," _" :" tert" },{" #name" :" __text__" ," _" :" -butoxycarbonyl Ms" },{" #name" :" keyword" ," $" :{" id" :" k0105" }," $$" :[{" #name" :" text" ," _" :" methanesulfonyl IBX" },{" #name" :" keyword" ," $" :{" id" :" k0115" }," $$" :[{" #name" :" text" ," _" :" 2-iodoxybenzoic acid T3P®" },{" #name" :" keyword" ," $" :{" id" :" k0125" }," $$" :[{" #name" :" text" ," _" :" propylphosphonic acid anhydride DIPEA" },{" #name" :" keyword" ," $" :{" id" :" k0135" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" ," },{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" -diisopropylethylamine CDI" },{" #name" :" keyword" ," $" :{" id" :" k0145" }," $$" :[{" #name" :" text" ," _" :" 1,1′-carbonyldiimidazole PPL" },{" #name" :" keyword" ," $" :{" id" :" k0155" }," $$" :[{" #name" :" text" ," _" :" lipase from Porcine Pancreas MTBE" },{" #name" :" keyword" ," $" :{" id" :" k0165" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" __text__" ," _" :" methyl " },{" #name" :" italic" ," _" :" tert" },{" #name" :" __text__" ," _" :" -butyl ether REMD" },{" #name" :" keyword" ," $" :{" id" :" k0175" }," $$" :[{" #name" :" text" ," _" :" replica-exchange molecular dynamics CYP" },{" #name" :" keyword" ," $" :{" id" :" k0185" }," $$" :[{" #name" :" text" ," _" :" cytochrome P450 CHO" },{" #name" :" keyword" ," $" :{" id" :" k0195" }," $$" :[{" #name" :" text" ," _" :" Chinese hamster ovary ER" },{" #name" :" keyword" ," $" :{" id" :" k0205" }," $$" :[{" #name" :" text" ," _" :" efflux ratio P-gp" },{" #name" :" keyword" ," $" :{" id" :" k0215" }," $$" :[{" #name" :" text" ," _" :" P-glycoprotein RHS" },{" #name" :" keyword" ," $" :{" id" :" k0225" }," $$" :[{" #name" :" text" ," _" :" right hand side PPB" },{" #name" :" keyword" ," $" :{" id" :" k0235" }," $$" :[{" #name" :" text" ," _" :" plasma protein binding CSF" },{" #name" :" keyword" ," $" :{" id" :" k0245" }," $$" :[{" #name" :" text" ," _" :" cerebrospinal fluid MED" },{" #name" :" keyword" ," $" :{" id" :" k0255" }," $$" :[{" #name" :" text" ," _" :" minimum effective dose |
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