1. Design, synthesis and biological characterization of selective LIMK inhibitors.
- Author
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Boland, Sandro, Bourin, Arnaud, Alen, Jo, Geraets, Jacques, Schroeders, Pieter, Castermans, Karolien, Kindt, Nele, Boumans, Nicki, Panitti, Laura, Vanormelingen, Jessica, Fransen, Silke, Van de Velde, Sarah, and Defert, Olivier
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GLAUCOMA , *CANCER , *DRUGS , *CLINICAL trials , *HIV infections - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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