title: Design, synthesis, and biological evaluation of novel, highly active soft ROCK inhibitors.
abstract: ROCK1 and ROCK2 play important roles in numerous cellular functions, including smooth muscle cell contraction, cell proliferation, adhesion, and migration. Consequently, ROCK inhibitors are of interest for treating multiple indications including cardiovascular diseases, inflammatory and autoimmune diseases, lung diseases, and eye diseases. However, systemic inhibition of ROCK is expected to result in significant side effects. Strategies allowing reduced systemic exposure are therefore of interest. In a continuing effort toward identification of ROCK inhibitors, we here report the design, synthesis, and evaluation of novel soft ROCK inhibitors displaying an ester function allowing their rapid inactivation in the systemic circulation. Those compounds display subnanomolar activity against ROCK and strong differences of functional activity between parent compounds and expected metabolites. The binding mode of a representative compound was determined experimentally in a single-crystal X-ray diffraction study. Enzymes responsible for inactivation of these compounds once they enter systemic circulation are also discussed.
authors.affiliation: †Amakem Therapeutics, Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Sandro
authors.initials: S
authors.lastname: Boland
authors.affiliation: †Amakem Therapeutics, Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Bourin
authors.affiliation: †Amakem Therapeutics, Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Alen
authors.affiliation: †Amakem Therapeutics, Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Jacques
authors.initials: J
authors.lastname: Geraets
authors.affiliation: †Amakem Therapeutics, Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Schroeders
authors.affiliation: †Amakem Therapeutics, Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Karolien
authors.initials: K
authors.lastname: Castermans
authors.affiliation: †Amakem Therapeutics, Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Nele
authors.initials: N
authors.lastname: Kindt
authors.affiliation: †Amakem Therapeutics, Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Nicki
authors.initials: N
authors.lastname: Boumans
authors.affiliation: †Amakem Therapeutics, Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Laura
authors.initials: L
authors.lastname: Panitti
authors.affiliation: †Amakem Therapeutics, Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Silke
authors.initials: S
authors.lastname: Fransen
authors.affiliation: †Amakem Therapeutics, Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Jessica
authors.initials: J
authors.lastname: Vanormelingen
authors.affiliation: †Amakem Therapeutics, Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Stassen
authors.affiliation: ‡CSD Farmakem, Elvire Boelensstraat 7, 9160 Lokeren, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Leysen
authors.affiliation: †Amakem Therapeutics, Agoralaan Abis, 3590 Diepenbeek, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Defert
mesh_terms: D000818:Animals; D018938:Caco-2 Cells / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004355:Drug Stability; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D047428:Protein Kinase Inhibitors; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases