IOP-lowering effect of isoquinoline-5-sulfonamide compounds in ocular normotensive monkeys

  • Bioorg Med Chem Lett. 2014 Feb 1;24(3):831-4. doi: 10.1016/j.bmcl.2013.12.085.
Kengo Sumi  1 ,  Yoshihiro Inoue  1 ,  Masahiro Nishio  2 ,  Yasuhito Naito  3 ,  Takamitsu Hosoya  4 ,  Masaaki Suzuki  5 ,  Hiroyoshi Hidaka  6
Affiliations
  • 1. D. Western Therapeutics Inc., 1-18-11 Nishiki, Naka-ku, Nagoya, Aichi 460-0003, Japan.
  • 2. Department of Sustainable Resource Science, Graduate School of Bioresources, Mie University, 2-174, Edobashi, Tsu, Mie 514-8507, Japan.
  • 3. Department of Pharmacology, School of Pharmaceutical Science, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
  • 4. 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.
  • 5. RIKEN Center for Molecular Imaging Science, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
  • 6. D. Western Therapeutics Inc., 1-18-11 Nishiki, Naka-ku, Nagoya, Aichi 460-0003, Japan. Electronic address: [email protected].
PMID: 24412071 DOI: 10.1016/j.bmcl.2013.12.085
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.

Keywords
Antiglaucoma agent; H-1152; Intraocular pressure (IOP)-lowering effect; Isoquinoline sulfonamide; ROCK inhibitor.
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