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  • Title: Synthesis and biological evaluation of urea derivatives as highly potent and selective rho kinase inhibitors.
    Author: Yin Y, Lin L, Ruiz C, Khan S, Cameron MD, Grant W, Pocas J, Eid N, Park H, Schröter T, Lograsso PV, Feng Y.
    Journal: J Med Chem; 2013 May 09; 56(9):3568-81. PubMed ID: 23570561.
    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.
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