Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors

Ray, Peter C.; Wright, Jane; Adam, Jennifer; Bennett, Johnathan; Boucharens, Sylviane; Black, D. StC.; Cook, Andrew; Brown, Angus R.; Epemolu, Ola; Fletcher, Dan; Haunsø, Anders; Huggett, Margaret; Jones, Phillip W.; Laats, Steven; Lyons, Amanda; Mestres, Jordi; Man, Jos de; Morphy, Richard; Rankovic, Zoran; Sherborne, Brad; Sherry, Lorcan; Straten, Nicole van; Westwood, Paul; Zaman, Guido Z.R.

doi:10.1016/j.bmcl.2010.11.060

Cited by 27 publications

(26 citation statements)

References 28 publications

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“…Various classic approaches of screening as well as fragment-based drug discovery methods and optimization have led to the identification of compounds with different selectivity for ROCK1 and ROCK2 (Boerma et al, 2008;Ray et al, 2011;Li et al, 2012b). Among them, KD-025 [2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl) phenoxy)-N-isopropylacetamide; formerly SLx-2119] was the first and remains the only ATP-competitive isoform-selective ROCK2 inhibitor.…”

Section: A Rho-associated Kinase Inhibitorsmentioning

confidence: 99%

Rho Kinases in Health and Disease: From Basic Science to Translational Research

Loirand¹

2015

Pharmacol Rev

161

133

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Section: A Rho-associated Kinase Inhibitorsmentioning

confidence: 99%

Rho Kinases in Health and Disease: From Basic Science to Translational Research

Loirand¹

2015

Pharmacol Rev

161

133

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“…Due to potential therapeutic applications, significant research efforts have been directed towards the identification of more potent and more selective ROCK inhibitors, 38–43 including isoquinolinamines 44,45 triazines, 46 isoquinolinones, 47,48 quinazolinones, 49 benzothiazoles 50 and diaminopyrazines 51 and their use for the treatment of cardiovascular diseases and CNS disorders. To the best of our knowledge the antitumor and antimetastatic properties of these inhibitors has yet to be shown or published.…”

Section: Introductionmentioning

confidence: 99%

Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2)

et al. 2012

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Potent ROCK inhibitors of a new class of 1-benzyl-3-(4-pyridylthiazol-2-yl)ureas have been identified. Remarkable differences in activity were observed for ureas bearing a benzylic stereogenic center. Derivatives with hydroxy, methoxy and amino groups at the meta position of the phenyl ring give rise to the most potent inhibitors (low nM). Substitutions at the para position result in substantial loss of potency. Changes at the benzylic position are tolerated resulting in significant potency in the case of methyl and methylenehydroxy groups. X-Ray crystallography was used to establish the binding mode of this class of inhibitors and provides an explanation for the observed differences of the enantiomer series. Potent inhibition of ROCK in human lung cancer cells was shown by suppression of the levels of phosphorylation of the ROCK substrate MYPT-1.

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“… a IC 50 values unless otherwise noted. b References R-1 115 , R-2 272 , R-3 109 , R-4, 119 R-5 126 , R-6, 129 R-7, 129 R-8, 109, 141 R-9, 130 R-10, 131 R-11, 156 R-12, 157 R-13 157 . c Tested in perfusion studies. N/A: not available.…”

Section: Figurementioning

confidence: 99%

Discovery of Molecular Therapeutics for Glaucoma: Challenges, Successes, and Promising Directions

Donegan

Lieberman

2015

J. Med. Chem.

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Glaucoma, a heterogeneous ocular disorder affecting ~60 million people worldwide, is characterized by painless neurodegeneration of retinal ganglion cells (RGCs), resulting in irreversible vision loss. Available therapies, which decrease the common causal risk factor of elevated intraocular pressure, delay, but cannot prevent, RGC death and blindness. Notably, it is changes in the anterior segment of the eye, particularly in the drainage of aqueous humor fluid, which are believed to bring about changes in pressure. Thus, it is primarily this region whose properties are manipulated in current and emerging therapies for glaucoma. Here, we focus on the challenges associated with developing treatments, review the available experimental methods to evaluate the therapeutic potential of new drugs, describe the development and evaluation of emerging Rho-kinase inhibitors and adenosine receptor ligands that offer the potential to improve aqueous humor outflow and protect RGCs simultaneously, and present new targets and approaches on the horizon.

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Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors

Cited by 27 publications

References 28 publications

Rho Kinases in Health and Disease: From Basic Science to Translational Research

Rho Kinases in Health and Disease: From Basic Science to Translational Research

Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2)

Discovery of Molecular Therapeutics for Glaucoma: Challenges, Successes, and Promising Directions

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