Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists.
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.
Department of Medicinal Chemistry, School of Pharmacy, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Takashi
T
Nagahara
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Tsuyoshi
T
Saitoh
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Noriki
N
Kutsumura
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Yoko
Y
Irukayama-Tomobe
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Yasuhiro
Y
Ogawa
School of Pharmacy, Showa University , 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
Daisuke
D
Kuroda
School of Pharmacy, Showa University , 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
Hiroaki
H
Gouda
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.|Department of Molecular Genetics, University of Texas Southwestern Medical Center , Dallas, Texas 75390-8584, United States.
Hidetoshi
H
Kumagai
Department of Medicinal Chemistry, School of Pharmacy, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Hideaki
H
Fujii
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.|Department of Molecular Genetics, University of Texas Southwestern Medical Center , Dallas, Texas 75390-8584, United States.
Masashi
M
Yanagisawa
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.|Department of Medicinal Chemistry, School of Pharmacy, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Hiroshi
H
Nagase
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002385:Cataplexy / Q000188:drug therapy; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D057166:High-Throughput Screening Assays; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009290:Narcolepsy / Q000188:drug therapy; D064446:Orexin Receptors / Q000819:agonists*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D014961:X-Ray Diffraction
C000604571:4'-methoxy-N,N-dimethyl-3'-(N-(3-((2-(3-methylbenzamido)ethyl)amino)phenyl)sulfamoyl)-(1,1'-biphenyl)-3-carboxamide; D001549:Benzamides; D064446:Orexin Receptors; D054852:Small Molecule Libraries; D013449:Sulfonamides; D002118:Calcium