Design, synthesis and biological characterization of selective LIMK inhibitors

被引：22

作者：

Boland, Sandro ^{[1
]}

Bourin, Arnaud ^{[1
]}

Alen, Jo ^{[1
]}

Geraets, Jacques ^{[1
]}

Schroeders, Pieter ^{[1
]}

Castermans, Karolien ^{[1
]}

Kindt, Nele ^{[1
]}

Boumans, Nicki ^{[1
]}

Panitti, Laura ^{[1
]}

Vanormelingen, Jessica ^{[1
]}

Fransen, Silke ^{[1
]}

Van de Velde, Sarah ^{[2
]}

Defert, Olivier ^{[1
]}

机构：

[1] Amakem Therapeut NV, B-3590 Diepenbeek, Belgium

[2] Katholieke Univ Leuven, Lab Ophthalmol, B-3000 Leuven, Belgium

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 18期

关键词：

Kinase inhibitor; LIMK; ROCK; SAR; LX-7101; PROTEIN-KINASE; IDENTIFICATION; DISCOVERY; PHOSPHORYLATION; FAMILY;

D O I：

10.1016/j.bmcl.2015.07.009

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibitors of LIM kinases are considered of interest for several indications, including elevated intraocular pressure (IOP), cancer, or infection by HIV-1. LX-7101 (Lexicon Pharmaceuticals) was advanced to Phase-I clinical trials as an IOP-lowering agent for treatment of glaucoma. We here discuss the design, synthesis and evaluation of LIMK inhibitors based on a pyrrolopyrimidine scaffold, which represent close analogs of LX-7101. Exploration of structure-activity relationships revealed that many of such compounds, including LX-7101, cause potent inhibition of LIMK1 and LIMK2, and also ROCK2 and PKA. Molecular variations around the various structural elements of LX-7101 were attempted. Substitution on position 6 of the pyrrolopyrimidine scaffold led to the identification of LX-7101 analogs displaying good selectivity versus ROCK, PKA and Akt. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：4005 / 4010

页数：6

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