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.
Sandro Boland  1 ,  Arnaud Bourin  2 ,  Jo Alen  2 ,  Jacques Geraets  2 ,  Pieter Schroeders  2 ,  Karolien Castermans  2 ,  Nele Kindt  2 ,  Nicki Boumans  2 ,  Laura Panitti  2 ,  Jessica Vanormelingen  2 ,  Silke Fransen  2 ,  Sarah Van de Velde  3 ,  Olivier Defert  2
Affiliations
  • 1. Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium. Electronic address: [email protected].
  • 2. Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium.
  • 3. Laboratory of Ophthalmology, KU Leuven, 3000 Leuven, Belgium.
PMID: 26233434 DOI: 10.1016/j.bmcl.2015.07.009
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.
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