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

被引：22

作者：

Sumi, Kengo ^{[1
]}

Inoue, Yoshihiro ^{[1
]}

Nishio, Masahiro ^{[2
]}

Naito, Yasuhito ^{[3
]}

Hosoya, Takamitsu ^{[4
]}

Suzuki, Masaaki ^{[5
]}

Hidaka, Hiroyoshi ^{[1
]}

机构：

[1] D Western Therapeut Inc, Naka Ku, Nagoya, Aichi 4600003, Japan

[2] Mie Univ, Grad Sch Bioresources, Dept Sustainable Resource Sci, Tsu, Mie 5148507, Japan

[3] Kitasato Univ, Sch Pharmaceut Sci, Dept Pharmacol, Minato Ku, Tokyo 1088641, Japan

[4] Tokyo Med & Dent Univ, Inst Biomat & Bioengn, Lab Chem Biosci, Chiyoda Ku, Tokyo 1010062, Japan

[5] RIKEN, Ctr Mol Imaging Sci, Chuo Ku, Kobe, Hyogo 6500047, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 03期

关键词：

ROCK inhibitor; H-1152; Antiglaucoma agent; Isoquinoline sulfonamide; Intraocular pressure (IOP)-lowering effect; PROTEIN-KINASE INHIBITOR; HUMOR OUTFLOW FACILITY; RHO-KINASE; INTRAOCULAR-PRESSURE; TRABECULAR MESHWORK; COMBINATION THERAPY; HUMAN EYES; GLAUCOMA; HYPERTENSION; TIMOLOL;

D O I：

10.1016/j.bmcl.2013.12.085

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2014 Elsevier Ltd. All rights rights reserved.

引用

页码：831 / 834

页数：4

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