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

Academic Article
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Overview

authors

  • Yin, Y.
  • Zheng, K.
  • Eid, N.
  • Howard, S.
  • Jeong, J. H.
  • Yi, F.
  • Guo, J.
  • Park, C. M.
  • Bibian, M.
  • Wu, W.
  • Hernandez, P.
  • Park, HaJeung
  • Wu, Y.
  • Luo, Junli
  • LoGrasso, Philip
  • Feng, Yangbo

publication date

  • February 2015

journal

  • Journal of Medicinal Chemistry  Journal

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 ?M), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compound 18b at 1 ?M 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.
  • 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.

subject areas

  • Animals
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Humans
  • Lim Kinases
  • Microsomes, Liver
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors
  • Rats
  • Structure-Activity Relationship
  • Urea
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Identity

PubMed Central ID

  • PMC4349585

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm501680m

PubMed ID

  • 25621531
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Additional Document Info

start page

  • 1846

end page

  • 1861

volume

  • 58

issue

  • 4

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