Discovery of Potent and Selective Urea-Based ROCK Inhibitors and Their Effects on Intraocular Pressure in Rats

被引：38

作者：

Yin, Yan ^{[1
,2
]}

Cameron, Michael D. ^{[1
,2
]}

Lin, Li ^{[1
,2
]}

Khan, Susan ^{[1
,2
]}

Schroeter, Thomas ^{[1
,2
]}

Grant, Wayne ^{[1
,2
]}

Pocas, Jennifer ^{[1
,2
]}

Chen, Yen Ting ^{[1
,2
]}

Schuerer, Stephan ^{[3
,4
]}

Pachori, Alok ^{[1
,2
]}

LoGrasso, Philip ^{[1
,2
]}

Feng, Yangbo ^{[1
,2
]}

机构：

[1] Translat Res Inst, Jupiter, FL 33458 USA

[2] Dept Mol Therapeut, Jupiter, FL 33458 USA

[3] Univ Miami, Dept Pharmacol, Miami, FL 33136 USA

[4] Univ Miami, Ctr Computat Sci, Miami, FL 33136 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2010年 / 1卷 / 04期

关键词：

Glaucoma; ROCK; IOP; kinase inhibitor; urea; pyrazole; PROTEIN-KINASE INHIBITOR; RHO; PHOSPHORYLATION;

D O I：

10.1021/ml1000382

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of urea-based Rho kinase (ROCK) inhibitors were designed and evaluated. The discovered compounds had excellent enzyme and cellular potency, high kinase selectivity, high aqueous solubility, good porcine corneal penetration, and appropriate DMPK profiles for topical applications as antiglaucoma therapeutics.

引用

页码：175 / 179

页数：5

共 18 条

[1] MECHANISM OF TIMOLOL IN LOWERING INTRA-OCULAR PRESSURE - IN NORMAL EYE [J].

COAKES, RL ;

BRUBAKER, RF .

ARCHIVES OF OPHTHALMOLOGY, 1978, 96 (11) :2045-2048

[2] Discovery of Substituted 4-(Pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as Potent and Highly Selective Rho Kinase (ROCK-II) Inhibitors [J].

Feng, Yangbo ;

Yin, Yan ;

Weiser, Arniee ;

Griffin, Evelyn ;

Cameron, Michael D. ;

Lin, Li ;

Ruiz, Claudia ;

Schuerer, Stephan C. ;

Inoue, Toshihiro ;

Rao, P. Vasanth ;

Schroeter, Thomas ;

LoGrasso, Philip .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (21) :6642-6645

[3] Inhibition of Rho-kinase-induced myristoylated alanine-rich C kinase substrate (MARCKS) phosphorylation in human neuronal cells by H-1152, a novel and specific Rho-kinase inhibitor [J].

Ikenoya, M ;

Hidaka, H ;

Hosoya, T ;

Suzuki, M ;

Yamamoto, N ;

Sasaki, Y .

JOURNAL OF NEUROCHEMISTRY, 2002, 81 (01) :9-16

[4] DOSE-RESPONSE AND DURATION OF ACTION OF DORZOLAMIDE, A TOPICAL CARBONIC-ANHYDRASE INHIBITOR [J].

LIPPA, EA ;

CARLSON, LE ;

EHINGER, B ;

ERIKSSON, LO ;

FINNSTROM, K ;

HOLMIN, C ;

NILSSON, SEG ;

NYMAN, K ;

RAITTA, C ;

RINGVOLD, A ;

TARKKANEN, A ;

VEGGE, T ;

DEASY, D ;

HOLDER, D ;

YTTEBORG, J .

ARCHIVES OF OPHTHALMOLOGY, 1992, 110 (04) :495-499

[5] ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice [J].

Nakagawa, O ;

Fujisawa, K ;

Ishizaki, T ;

Saito, Y ;

Nakao, K ;

Narumiya, S .

FEBS LETTERS, 1996, 392 (02) :189-193

[6] Contribution of ROCK in contraction of trabecular meshwork: Proposed mechanism for regulating aqueous outflow in monkey and human eyes [J].

Nakajima, E ;

Nakajima, T ;

Minagawa, Y ;

Shearer, TR ;

Azuma, M .

JOURNAL OF PHARMACEUTICAL SCIENCES, 2005, 94 (04) :701-708

[7] The Effect of the H-1152P, a Potent Rho-Associated Coiled Coil-Formed Protein Kinase Inhibitor, in Rabbit Normal and Ocular Hypertensive Eyes [J].

Nishio, Masahiro ;

Sumi, Kengo ;

Hidaka, Hiroyoshi ;

Fukunaga, Takaki ;

Sugimoto, Masahiko ;

Ikesugi, Kengo ;

Uji, Yukitaka .

CURRENT EYE RESEARCH, 2009, 34 (04) :282-286

[8] Acute effects of glaucoma medications on rat intraocular pressure [J].

Pang, IH ;

Wang, WH ;

Clark, AF .

EXPERIMENTAL EYE RESEARCH, 2005, 80 (02) :207-214

[9] Rodent models for glaucoma retinopathy and optic neuropathy [J].

Pang, Iok-Hou ;

Clark, Abbot F. .

JOURNAL OF GLAUCOMA, 2007, 16 (05) :483-505

[10] The number of people with glaucoma worldwide in 2010 and 2020 [J].

Quigley, HA ;

Broman, AT .

BRITISH JOURNAL OF OPHTHALMOLOGY, 2006, 90 (03) :262-267

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