2. Academic Validation
  3. Bis-aryl urea derivatives as potent and selective LIM kinase (Limk) inhibitors

Bis-aryl urea derivatives as potent and selective LIM kinase (Limk) inhibitors

  • J Med Chem. 2015 Feb 26;58(4):1846-61. doi: 10.1021/jm501680m.
Yan Yin 1,  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

Affiliation

  • 1 Medicinal Chemistry, ‡Discovery Biology, §Crystallography/Modeling Facility, Translational Research Institute, ∥Department of Molecular Therapeutics, and ⊥Department of Cancer Biology, The Scripps Research Institute, Scripps Florida , 130 Scripps Way, No. 2A1, Jupiter, Florida 33458, United States.
PMID: 25621531 DOI: 10.1021/jm501680m
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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