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

Design, synthesis and biological characterization of selective LIMK inhibitors.

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Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium. Electronic address:
Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium.
Laboratory of Ophthalmology, KU Leuven, 3000 Leuven, Belgium.


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.


Kinase inhibitor; LIMK; LX-7101; ROCK; SAR

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