title: IOP-lowering effect of isoquinoline-5-sulfonamide compounds in ocular normotensive monkeys.
abstract: Rho-associated coiled coil-formed protein kinase (ROCK) inhibitors are under development as a new class of antiglaucoma agents. Based on the potent ROCK inhibitor H-1152, previously developed by us, we explored the possibility of related compounds as antiglaucoma agents and synthesized seven types of H-1152-inspired isoquinoline-5-sulfonamide compounds (H-0103-H-0107, H-1001, H-1005). Although all of these compounds potently inhibited ROCK (IC50=18-48 nM), only H-0104 and H-0106 exerted strong intraocular pressure (IOP)-lowering effects into the eyes of monkeys. These results suggested the possibility that there is no direct relationship between ROCK inhibition and IOP-lowering effects, indicating that the initial screening of compounds based on ROCK inhibitory activity may be an unsuitable strategy for developing antiglaucoma agents with potent IOP-lowering effects.
authors.affiliation: D. Western Therapeutics Inc., 1-18-11 Nishiki, Naka-ku, Nagoya, Aichi 460-0003, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Sumi
authors.affiliation: D. Western Therapeutics Inc., 1-18-11 Nishiki, Naka-ku, Nagoya, Aichi 460-0003, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Sustainable Resource Science, Graduate School of Bioresources, Mie University, 2-174, Edobashi, Tsu, Mie 514-8507, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishio
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Science, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Naito
authors.affiliation: Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Hosoya
authors.affiliation: RIKEN Center for Molecular Imaging Science, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: D. Western Therapeutics Inc., 1-18-11 Nishiki, Naka-ku, Nagoya, Aichi 460-0003, Japan. Electronic address: hihidaka@dwti.co.jp.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Hidaka
mesh_terms: D000818:Animals; D005901:Glaucoma / Q000188:drug therapy; D000882:Haplorhini; D020128:Inhibitory Concentration 50; D007429:Intraocular Pressure / Q000187:drug effects*; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000737:chemistry / Q000378:metabolism
chemical_list: D007546:Isoquinolines; D013449:Sulfonamides; C508673:isoquinoline-5-sulfonamide; D054460:rho-Associated Kinases
keywords: Antiglaucoma agent; H-1152; Intraocular pressure (IOP)-lowering effect; Isoquinoline sulfonamide; ROCK inhibitor