Design, synthesis and biological characterization of selective LIMK inhibitors

Bioorg Med Chem Lett. 2015 Sep 15;25(18):4005-10. doi: 10.1016/j.bmcl.2015.07.009. Epub 2015 Jul 10.

Abstract

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.

Keywords: Kinase inhibitor; LIMK; LX-7101; ROCK; SAR.

MeSH terms

  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HeLa Cells
  • Humans
  • Lim Kinases / antagonists & inhibitors*
  • Lim Kinases / metabolism
  • Models, Molecular
  • Molecular Structure
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship
  • rho-Associated Kinases / antagonists & inhibitors*
  • rho-Associated Kinases / metabolism

Substances

  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • LX-7101
  • Lim Kinases
  • ROCK2 protein, human
  • rho-Associated Kinases
  • Cyclic AMP-Dependent Protein Kinases