Bis-aryl Urea Derivatives As Potent and Selective LIM Kinase (Limk) Inhibitors

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2015 Jan 27

PMID 25621531

Citations 22

Authors

Yan Yin

Ke Zheng

Nibal Eid

Shannon Howard

Ji-Hak Jeong

Fei Yi

Jia Guo

Chul Min Park

Mathieu Bibian

Weilin Wu

Pamela Hernandez

HaJeung Park

Yuntao Wu

Jun-Li Luo

Philip V LoGrasso

Yangbo Feng

Affiliations

Soon will be listed here.

Abstract

The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the observed SAR. Optimized Limk inhibitors had high biochemical potency (IC50 < 25 nM), excellent selectivity against ROCK and JNK kinases (>400-fold), potent inhibition of cofilin phosphorylation in A7r5, PC-3, and CEM-SS T cells (IC50 < 1 μM), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compound 18b at 1 μM inhibited only Limk1 and STK16 with ≥80% inhibition. Compounds 18b and 18f were highly efficient in inhibiting cell-invasion/migration in PC-3 cells. In addition, compound 18w was demonstrated to be effective on reducing intraocular pressure (IOP) on rat eyes. Taken together, these data demonstrated that we had developed a novel class of bis-aryl urea derived potent and selective Limk inhibitors.

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