Design, synthesis and biological characterization of selective LIMK inhibitors
S Boland, A Bourin, J Alen, J Geraets… - Bioorganic & Medicinal …, 2015 - Elsevier
S Boland, A Bourin, J Alen, J Geraets, P Schroeders, K Castermans, N Kindt, N Boumans…
Bioorganic & Medicinal Chemistry Letters, 2015•ElsevierInhibitors 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 …
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 …
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.
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