title: Design, synthesis and biological characterization of selective LIMK inhibitors.
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.
authors.affiliation: Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium. Electronic address: sandro.boland@amakem.com.
authors.forename: Sandro
authors.initials: S
authors.lastname: Boland
authors.affiliation: Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Bourin
authors.affiliation: Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Alen
authors.affiliation: Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Jacques
authors.initials: J
authors.lastname: Geraets
authors.affiliation: Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Schroeders
authors.affiliation: Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Karolien
authors.initials: K
authors.lastname: Castermans
authors.affiliation: Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Nele
authors.initials: N
authors.lastname: Kindt
authors.affiliation: Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Nicki
authors.initials: N
authors.lastname: Boumans
authors.affiliation: Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Laura
authors.initials: L
authors.lastname: Panitti
authors.affiliation: Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Jessica
authors.initials: J
authors.lastname: Vanormelingen
authors.affiliation: Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Silke
authors.initials: S
authors.lastname: Fransen
authors.affiliation: Laboratory of Ophthalmology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Van de Velde
authors.affiliation: Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Defert
mesh_terms: D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D054461:Lim Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000607841:LX-7101; D054461:Lim Kinases; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Kinase inhibitor; LIMK; LX-7101; ROCK; SAR