Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists

• Published in: Journal of medicinal chemistry Vol. 58; no. 20; pp. 7931 - 7937
• Main Authors: Nagahara, Takashi, Saitoh, Tsuyoshi, Kutsumura, Noriki, Irukayama-Tomobe, Yoko, Ogawa, Yasuhiro, Kuroda, Daisuke, Gouda, Hiroaki, Kumagai, Hidetoshi, Fujii, Hideaki, Yanagisawa, Masashi, Nagase, Hiroshi
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 22-10-2015
• Subjects: Animals; Benzamides - chemical synthesis; Benzamides - pharmacology; Calcium - metabolism; Cataplexy - drug therapy; Cell Line, Tumor; CHO Cells; Cricetinae; Cricetulus; Drug Design; High-Throughput Screening Assays; Humans; Hydrogen Bonding; Models, Molecular; Narcolepsy - drug therapy; Orexin Receptors - agonists; Small Molecule Libraries; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; X-Ray Diffraction
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00988

Orexins are a family of neuropeptides that regulate sleep/wakefulness, acting on two G-protein-coupled receptors, orexin receptors 1 (OX1R) and 2 (OX2R). Genetic and pharmacologic evidence suggests that orexin receptor agonists, especially OX2R agonist, will be useful for mechanistic therapy of the sleep disorder narcolepsy/cataplexy. We herein report the discovery of a potent (EC50 on OX2R is 0.023 μM) and OX2R-selective (OX1R/OX2R EC50 ratio is 70) agonist, 4′-methoxy-N,N-dimethyl-3′-[N-(3-{[2-(3-methylbenzamido)­ethyl]­amino}­phenyl)­sulfamoyl]-(1,1′-biphenyl)-3-carboxamide 26.