Optimisation of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors

Ray, Peter C.; Wright, Jane; Adam, Jennifer; Boucharens, Sylviane; Black, D. StC.; Brown, Angus R.; Epemolu, Ola; Fletcher, Dan; Huggett, Margaret; Jones, Phillip W.; Laats, Steven; Lyons, Amanda; Man, Jos de; Morphy, Richard; Sherborne, Brad; Sherry, Lorcan; Straten, Nicole van; Westwood, Paul; York, Mark

doi:10.1016/j.bmcl.2010.12.104

Cited by 18 publications

(16 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most of these novel inhibitors, also targeting the ROCK ATP pocket, are non-isoform selective. 114–124 The resolution of crystal structure of ROCK1 complexes with inhibitors helps to improve the selectivity and potency of novel inhibitors. 125 Recent efforts have also been devoted to developing isoform-selective inhibitors.…”

Section: Development and Therapeutic Effects Of Rock Inhibitorsmentioning

confidence: 99%

Rho Kinases in Cardiovascular Physiology and Pathophysiology

Shi

Wei

2013

Journal of Cardiovascular Pharmacology

135

View full text Add to dashboard Cite

Summary Rho kinase (ROCK) is a major downstream effector of the small GTPase RhoA. ROCK family, consisting of ROCK1 and ROCK2, plays central roles in the organization of actin cytoskeleton and is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, proliferation, and apoptosis. Due to the discovery of effective inhibitors such as fasudil and Y27632, the biological roles of ROCK have been extensively explored with particular attention on the cardiovascular system. In many preclinical models of cardiovascular diseases including vasospasm, arteriosclerosis, hypertension, pulmonary hypertension, stroke, ischemia-reperfusion injury and heart failure, ROCK inhibitors have shown a remarkable efficacy in reducing vascular smooth muscle cell hypercontraction, endothelial dysfunction, inflammatory cell recruitment, vascular remodeling, and cardiac remodeling. Moreover, fasudil has been used in the clinical trials of several cardiovascular diseases. The continuing utilization of available pharmacological inhibitors and the development of more potent or isoform-selective inhibitors in ROCK signaling research and in treating human diseases are escalating. In this review, we discuss the recent molecular, cellular, animal and clinical studies with a focus on the current understanding of ROCK signaling in cardiovascular physiology and diseases. We particularly note that emerging evidence suggests that selective targeting ROCK isoform based on the disease pathophysiology may represent a novel therapeutic approach for the disease treatment including cardiovascular diseases.

show abstract

Section: Development and Therapeutic Effects Of Rock Inhibitorsmentioning

confidence: 99%

Rho Kinases in Cardiovascular Physiology and Pathophysiology

Shi

Wei

2013

Journal of Cardiovascular Pharmacology

135

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“… 22 , 30 , 31 Hydroxyfasudil has IC 50 values of 0.76 and 0.58 μM for ROCK1 and ROCK2, respectively ( Table 1 ). 32 In contrast, the IC 50 values for PARPs are well below their peak plasma concentration ( Table 1 and Figure 2 ). Therefore, PARP2 is unlikely to be involved in the mechanism of action of fasudil at these clinical concentrations.…”

Section: Resultsmentioning

confidence: 94%

Dual Inhibitors of PARPs and ROCKs

Antolín

Mestres

2018

ACS Omega

View full text Add to dashboard Cite

Recent network and system biology analyses suggest that most complex diseases are regulated by robust and highly interconnected pathways that could be better modulated by small molecules binding to multiple biological targets. These pieces of evidence recently led to devote efforts on identifying single chemical entities that bind to two different disease-relevant targets. Here, we first predicted in silico and later confirmed in vitro that UPF 1069, a known bioactive poly(ADP-ribose) polymerase-1/2 (PARP1/2) molecule, and hydroxyfasudil, a known bioactive Rho-associated protein kinase-1/2 (ROCK1/2) molecule, have low-micromolar cross-affinity for ROCK1/2 and PARP1/2, respectively. These molecules can now be regarded as chemical seeds from which pharmacological tools could be generated to study the impact of dual inhibition of PARPs and ROCKs in preclinical models of a variety of complex diseases where both targets are involved.

show abstract

Optimisation of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors

Cited by 18 publications

References 23 publications

Rho Kinases in Cardiovascular Physiology and Pathophysiology

Rho Kinases in Cardiovascular Physiology and Pathophysiology

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

Dual Inhibitors of PARPs and ROCKs

Contact Info

Product

Resources

About