title: 3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitors.
abstract: Clinical development of ROCK inhibitors has so far been limited by systemic or local ROCK-associated side effects. A soft drug approach, which involves predictable metabolic inactivation of an active compound to a nontoxic metabolite, could represent an attractive way to obtain ROCK inhibitors with improved tolerability. We herein report the design and synthesis of a new series of soft ROCK inhibitors structurally related to the ROCK inhibitor Y-27632. These inhibitors contain carboxylic ester moieties which allow inactivation by esterases. While the parent esters display strong activity in enzymatic (ROCK2) and cellular (MLC phosphorylation) assays, their corresponding carboxylic acid metabolites have negligible functional activity. Compound 32 combined strong efficacy (ROCK2 IC50=2.5 nM) with rapid inactivation in plasma (t1/2 <5'). Compound 32 also demonstrated in vivo efficacy when evaluated as an IOP-lowering agent in ocular normotensive New-Zealand White rabbits, without ocular side effects.
authors.affiliation: Amakem N.V. Agoralaan A bis, Diepenbeek 3590, Belgium. Electronic address: sandro.boland@amakem.com.
authors.forename: Sandro
authors.initials: S
authors.lastname: Boland
authors.forename: Olivier
authors.initials: O
authors.lastname: Defert
authors.forename: Jo
authors.initials: J
authors.lastname: Alen
authors.forename: Arnaud
authors.initials: A
authors.lastname: Bourin
authors.forename: Karolien
authors.initials: K
authors.lastname: Castermans
authors.forename: Nele
authors.initials: N
authors.lastname: Kindt
authors.forename: Nicki
authors.initials: N
authors.lastname: Boumans
authors.forename: Laura
authors.initials: L
authors.lastname: Panitti
authors.forename: Sarah
authors.initials: S
authors.lastname: Van de Velde
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Stalmans
authors.forename: Dirk
authors.initials: D
authors.lastname: Leysen
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D010766:Phosphorylation; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000577:Amides; D001565:Benzoates; D011725:Pyridines; C108830:Y 27632; D054460:rho-Associated Kinases
keywords: Esterase; Kinase inhibitor; ROCK; SAR; Soft drug