2. Academic Validation
  3. Design, synthesis and biological characterization of selective LIMK inhibitors

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12659
    99.75%, ROCK Inhibitor