- Design, synthesis and biological characterization of selective LIMK inhibitors
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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.
- 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,Defert, Olivier
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- LIMK2 INHIBITORS, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE
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Inhibitors of LIM kinase 2 are disclosed, along with pharmaceutical compositions comprising them and methods of their use. Particular compounds are of the formula:
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(2009/10/30)
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