title: Synthesis and biological evaluation of urea derivatives as highly potent and selective rho kinase inhibitors.
abstract: RhoA and its downstream effector ROCK mediate stress fiber formation and cell contraction through their effects on the phosphorylation of myosin light chain (MLC). Inhibition of the RhoA/ROCK pathway has proven to be a promising strategy for several indications such as cardiovascular disease, glaucoma, and inflammatory disease. In 2010, our group reported urea-based ROCK inhibitors as potential antiglaucoma agents. These compounds showed potent IC50 values in enzymatic and cell-based assays and significant intraocular pressure (IOP)-lowering effects in rats (∼7 mmHg). (22) To develop more advanced ROCK inhibitors targeting various potential applications (such as myocardial infarction, erectile dysfunction, multiple sclerosis, etc.) in addition to glaucoma, a thorough SAR for this urea-based scaffold was studied. The detailed optimization process, counter-screening, and in vitro and in vivo DMPK studies are discussed. Potent and selective ROCK inhibitors with various in vivo pharmacokinetic properties were discovered.
authors.affiliation: Medicinal Chemistry, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #2A1, Jupiter, Florida 33458, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yin
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Claudia
authors.initials: C
authors.lastname: Ruiz
authors.forename: Susan
authors.initials: S
authors.lastname: Khan
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.forename: Wayne
authors.initials: W
authors.lastname: Grant
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pocas
authors.forename: Nibal
authors.initials: N
authors.lastname: Eid
authors.forename: HaJeung
authors.initials: H
authors.lastname: Park
authors.forename: Thomas
authors.initials: T
authors.lastname: Schröter
authors.forename: Philip V
authors.initials: PV
authors.lastname: Lograsso
authors.forename: Yangbo
authors.initials: Y
authors.lastname: Feng
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014508:Urea / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D014508:Urea; D054460:rho-Associated Kinases