1. Academic Validation
  2. 3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitors

3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitors

  • Bioorg Med Chem Lett. 2013 Dec 1;23(23):6442-6. doi: 10.1016/j.bmcl.2013.09.040.
Sandro Boland 1 Olivier Defert Jo Alen Arnaud Bourin Karolien Castermans Nele Kindt Nicki Boumans Laura Panitti Sarah Van de Velde Ingeborg Stalmans Dirk Leysen
Affiliations

Affiliation

  • 1 Amakem N.V. Agoralaan A bis, Diepenbeek 3590, Belgium. Electronic address: sandro.boland@amakem.com.
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.

Keywords

Esterase; Kinase inhibitor; ROCK; SAR; Soft drug.

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