Substituted 2H-isoquinolin-1-one as potent Rho-Kinase inhibitors. Part 1: Hit-to-lead account

被引：16

作者：

Wu, Frank ^{[1
]}

Buttner, Frank H. ^{[4
]}

Chen, Rhonda ^{[2
]}

Hickey, Eugene ^{[1
]}

Jakes, Scott ^{[2
]}

Kaplita, Paul ^{[3
]}

Kashem, Mohammed A. ^{[1
]}

Kerr, Steven ^{[2
]}

Kugler, Stanley ^{[1
]}

Paw, Zofia ^{[2
]}

Prokopowicz, Anthony ^{[1
]}

Shih, Cheng-Kon ^{[2
]}

Snow, Roger ^{[1
]}

Young, Erick ^{[1
]}

Cywin, Charles L. ^{[1
]}

机构：

[1] Boehringer Ingelheim Pharmaceut Inc, Dept Med Chem, Ridgefield, CT 06877 USA

[2] Boehringer Ingelheim Pharmaceut Inc, Dept Cardiometab Dis, Ridgefield, CT 06877 USA

[3] Boehringer Ingelheim Pharmaceut Inc, Dept Drug Discovery Support, Ridgefield, CT 06877 USA

[4] Boehringer Ingelheim Pharma GmbH & Co KG, D-88397 Biberach, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 11期

关键词：

Rho-Kinase inhibitors; SMOOTH-MUSCLE-CELLS; PROTEIN-KINASE; SELECTIVITY; INVOLVEMENT; MECHANISM; Y-27632; COMPLEX; FASUDIL;

D O I：

10.1016/j.bmcl.2010.04.070

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Two closely related scaffolds were identified through an uHTS campaign as desirable starting points for the development of Rho-Kinase (ROCK) inhibitors. Here, we describe our hit-to-lead evaluation process which culminated in the rapid discovery of potent leads such as 22 which successfully demonstrated an early in vivo proof of concept for anti-hypertensive activity. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：3235 / 3239

页数：5

共 20 条

[1]

[Anonymous], MAESTR 8 0 314 GLIDE

[2] Protein kinase a in complex with rho-kinase inhibitors Y-27632, fasudil, and H-1152P: Structural basis of selectivity [J].

Breitenlechner, C ;

Gassel, M ;

Hidaka, H ;

Kinzel, V ;

Huber, R ;

Engh, RA ;

Bossemeyer, D .

STRUCTURE, 2003, 11 (12) :1595-1607

[3] Synthesis of novel substituted isoquinolones [J].

Briet, N ;

Brookes, MH ;

Davenport, RJ ;

Galvin, FCA ;

Gilbert, PJ ;

Mack, SR ;

Sabin, V .

TETRAHEDRON, 2002, 58 (29) :5761-5766

[4] Substituted isoquinolines and quinazolines as potential antiinflammatory agents.: Synthesis and biological evaluation of inhibitors of tumor necrosis factor α [J].

Chao, Q ;

Deng, L ;

Shih, HC ;

Leoni, LM ;

Genini, D ;

Carson, DA ;

Cottam, HB .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (19) :3860-3873

[5] Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities [J].

Doe, Chris ;

Bentley, Ross ;

Behm, David J. ;

Lafferty, Robert ;

Stavenger, Robert ;

Jung, David ;

Bamford, Mark ;

Panchal, Terry ;

Grygielko, Eugene ;

Wright, Lois L. ;

Smith, Gary K. ;

Chen, Zunxuan ;

Webb, Christine ;

Khandekar, Sanjay ;

Yi, Tracey ;

Kirkpatrick, Robert ;

Dul, Edward ;

Jolivette, Larry ;

Marino, Joseph P. ;

Willette, Robert ;

Lee, Dennis ;

Hu, Erding .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2007, 320 (01) :89-98

[6] SYNTHESIS OF FURO[3,2-C]PYRIDINES [J].

ELOY, F ;

DERYCKER.A .

JOURNAL OF HETEROCYCLIC CHEMISTRY, 1971, 8 (01) :57-&

[7] Crystal structures of catalytic subunit of cAMP-dependent protein kinase in complex with isoquinolinesulfonyl protein kinase inhibitors H7, H8, and H89 - Structural implications for selectivity [J].

Engh, RA ;

Girod, A ;

Kinzel, V ;

Huber, R ;

Bossemeyer, D .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (42) :26157-26164

[8] Rho kinase as potential therapeutic target for cardiovascular diseases: opportunities and challenges [J].

Hu, E ;

Lee, D .

EXPERT OPINION ON THERAPEUTIC TARGETS, 2005, 9 (04) :715-736

[9] The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase [J].

Ishizaki, T ;

Maekawa, M ;

Fujisawa, K ;

Okawa, K ;

Iwamatsu, A ;

Fujita, A ;

Watanabe, N ;

Saito, Y ;

Kakizuka, A ;

Morii, N ;

Narumiya, S .

EMBO JOURNAL, 1996, 15 (08) :1885-1893

[10] The structure of dimeric ROCK I reveals the mechanism for ligand selectivity [J].

Jacobs, M ;

Hayakawa, K ;

Swenson, L ;

Bellon, S ;

Fleming, M ;

Taslimi, P ;

Doran, J .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (01) :260-268

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