- Synthesis and biological evaluation of urea derivatives as highly potent and selective rho kinase inhibitors
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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.
- Yin, Yan,Lin, Li,Ruiz, Claudia,Khan, Susan,Cameron, Michael D.,Grant, Wayne,Pocas, Jennifer,Eid, Nibal,Park, Hajeung,Schr?ter, Thomas,Lograsso, Philip V.,Feng, Yangbo
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p. 3568 - 3581
(2013/06/27)
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- Discovery of potent and selective urea-based ROCK inhibitors and their effects on intraocular pressure in rats
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A series of urea-based Rho kinase (ROCK) inhibitors were designed and evaluated. The discovered compounds had excellent enzyme and cellular potency, high kinase selectivity, high aqueous solubility, good porcine corneal penetration, and appropriate DMPK profiles for topical applications as antiglaucoma therapeutics.
- Yin, Yan,Cameron, Michael D.,Lin, Li,Khan, Susan,Schroeter, Thomas,Grant, Wayne,Pocas, Jennifer,Chen, Yen Ting,Schuerer, Stephan,Pachori, Alok,Lograsso, Philip,Feng, Yangbo
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scheme or table
p. 175 - 179
(2010/10/21)
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- UREA AND CARBAMATE COMPOUNDS AND ANALOGS AS KINASE INHIBITORS
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The invention is directed to compounds that can inhibit the bioactivity of one or more kinases such as any of Rho kinases, PKB (Akt) kinases, p70S6K kinase, LIM kinases, or IKK kinases, to methods of use of those compounds, and to methods of preparation of those compounds The inventive compounds can be used In the treatment of a variety of medical malconditions.
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Page/Page column 50-51
(2010/04/27)
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- Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors
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The identification of a new class of potent and selective ROCK-II inhibitors is presented. Compound 5 (SR-3677) had an IC50 of ~3 nM in enzyme and cell based assays and had an off-target hit rate of 1.4% against 353 kinases, and inhibited only 3 out of 70 nonkinase enzymes and receptors. Pharmacology studies showed that 5 was efficacious in both, increasing ex vivo aqueous humor outflow in porcine eyes and inhibiting myosin light chain phosphorylation.
- Feng, Yangbo,Yin, Yan,Weiser, Amiee,Griffin, Evelyn,Cameron, Michael D.,Lin, Li,Ruiz, Claudia,Schürer, Stephan C.,Inoue, Toshihiro,Rao, P. Vasanth,Schr?ter, Thomas,LoGrasso, Philip
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supporting information; experimental part
p. 6642 - 6645
(2009/10/23)
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- Chroman-3-amides as potent Rho kinase inhibitors
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Inhibition of Rho kinase (ROCK) is an attractive strategy for the treatment of diseases such as hypertension, glaucoma, and cancer. Here we report chroman-3-amides as highly potent ROCK inhibitors with sufficient kinase selectivity, excellent cell activit
- Chen, Yen Ting,Bannister, Thomas D.,Weiser, Amiee,Griffin, Evelyn,Lin, Li,Ruiz, Claudia,Cameron, Michael D.,Schuerer, Stephan,Duckett, Derek,Schroeter, Thomas,LoGrasso, Philip,Feng, Yangbo
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scheme or table
p. 6406 - 6409
(2009/10/01)
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