Novel ROCK inhibitors for the treatment of pulmonary arterial hypertension

被引：31

作者：

Shaw, Duncan ^{[1
]}

Hollingworth, Greg ^{[1
]}

Soldermann, Nicolas ^{[2
]}

Sprague, Elizabeth ^{[3
]}

Schuler, Walter ^{[2
]}

Vangrevelinghe, Eric ^{[2
]}

Duggan, Nicholas ^{[1
]}

Thomas, Matthew ^{[1
]}

Kosaka, Takatoshi ^{[1
]}

Waters, Nigel ^{[1
]}

van Eis, Maurice J. ^{[2
]}

机构：

[1] Novartis Horsham Res Ctr, Horsham RH12 5AB, W Sussex, England

[2] Novartis Inst Biomed Res, CH-4056 Basel, Switzerland

[3] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 20期

关键词：

Rho kinase; Inhibitors; Lymphocyte depletion; Pulmonary arterial hypertension; Intra-tracheal dosing; RHO-KINASE INHIBITOR; PHYSIOLOGY; REVEALS;

D O I：

10.1016/j.bmcl.2014.09.002

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel class of selective inhibitors of ROCK1 and ROCK2 has been identified by structural based drug design. PK/PD experiments using a set of highly selective Rho kinase inhibitors suggest that systemic Rho kinase inhibition is linked to a reversible reduction in lymphocyte counts. These results led to the consideration of topical delivery of these molecules, and to the identification of a lead molecule 7 which shows promising PK and PD in a murine model of pulmonary hypertension after intra-tracheal dosing. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：4812 / 4817

页数：6

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