Cardiovascular effects of a novel selective Rho kinase inhibitor, 2-(1H-indazole-5-yl)amino-4-methoxy-6-piperazino triazine (DW1865)

Oh, Kwang‐Seok; Oh, Byung Koo; Park, Cheon Ho; Seo, Ho Won; Kang, Nam Sook; Lee, Jeong Hyun; Lee, Jin Soo; Lee, Byung Ho

doi:10.1016/j.ejphar.2013.01.027

Cited by 30 publications

(25 citation statements)

References 33 publications

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“…Several indazole compounds have been found to be active in Rho kinase inhibition [36,38] . Additionally, in our previous work, a new chemical entity, 5-nitro-1(2)H-indazole-3-carbonitrile (DL0805), was discovered as a new Rho kinase inhibitor with an IC 50 of 6.67 μmol/L.…”

Section: Discussionmentioning

confidence: 99%

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DL0805-2, a novel indazole derivative, relaxes angiotensin II-induced contractions of rat aortic rings by inhibiting Rho kinase and calcium fluxes

et al. 2016

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Aim: DL0805-2 [N-(1H-indazol-5-yl)-1-(4-methylbenzyl) pyrrolidine-3-carboxamide] is a DL0805 derivative with more potent vasorelaxant activity and lower toxicity. This study was conducted to investigate the vasorelaxant mechanisms of DL0805-2 on angiotensin II (Ang II)-induced contractions of rat thoracic aortic rings in vitro. Methods: Rat thoracic aortic rings and rat aortic vascular smooth muscle cells (VSMCs) were pretreated with DL0805-2, and then stimulated with Ang II. The tension of the aortic rings was measured through an isometric force transducer. Ang II-induced protein phosphorylation, ROS production and F-actin formation were assessed with Western blotting and immunofluorescence assays. Intracellular free Ca 2+ concentrations were detected with Fluo-3 AM. Results: Pretreatment with DL0805-2 (1-100 μmol/L) dose-dependently inhibited the constrictions of the aortic rings induced by a single dose of Ang II (10 -7 mol/L) or accumulative addition of Ang II (10 -10 -10 -7 mol/L). The vasodilatory effect of DL0805-2 was independent of endothelium. In the aortic rings, pretreatment with DL0805-2 (1, 3, and 10 μmol/L) suppressed Ang II-induced Ca 2+ influx and intracellular Ca 2+ mobilization, and Ang II-induced phosphorylation of two substrates of Rho kinase (MLC and MYPT1). In VSMCs, pretreatment with DL0805-2 (1, 3, and 10 μmol/L) also suppressed Ang II-induced Ca 2+ fluxes and phosphorylation of MLC and MYPT1. In addition, pretreatment with DL0805-2 attenuated ROS production and F-actin formation in the cells. Conclusion: DL0805-2 exerts a vasodilatory action in rat aortic rings through inhibiting the Rho/ROCK pathway and calcium fluxes.

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Section: Discussionmentioning

confidence: 99%

“…It is well known that actin stress fiber formation is induced by the activation of Rho kinase in several types of cells and tissues [36] . Thus, the cellular effect of DL0805-2 on actin stress fiber formation was tested in VSMCs.…”

Section: Dl0805-2 Inhibited F-actin Formation In Vsmcsmentioning

confidence: 99%

DL0805-2, a novel indazole derivative, relaxes angiotensin II-induced contractions of rat aortic rings by inhibiting Rho kinase and calcium fluxes

et al. 2016

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“…DW1865 resulted in a significant dose-related reduction in blood pressure. In addition, DW1865 blocked angiotensin II-induced stress fiber formation and cellular hypertrophy [46]. To date, there has been no reported study that investigated the benefits of DW1865 in angina patients.…”

Section: Investigational/ongoing Investigational Pharmacological Tmentioning

confidence: 99%

Experimental and early investigational drugs for angina pectoris

Elgendy

Winchester

Pepine

2016

Expert Opinion on Investigational Drugs

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Introduction Ischemic heart disease (IHD) is a major cause of death and disability among Western countries and angina pectoris is the most prevalent symptomatic manifestation. Strategies to improve management of chronic stable angina are a priority. Areas covered A comprehensive review was conducted using the Medline and Cochrane databases as well as the clinical trial databases in the United States and Europe. Traditional therapies for angina will be discussed. This review particularly emphasizes investigational therapies for angina (including pharmacological agents, cell and gene based therapies, and herbal medications). Expert commentary There has been renewed interest in older anti-angina agents (e.g., perhexiline, amiodarone, and phosphodiestrase-5 inhibitors). Other anti-inflammatory agents (e.g., allopurinol and febuxostat) are currently undergoing evaluation for angina therapy. Therapeutic angiogenesis continues to face some challenges. Future trials should evaluate the optimum patient population that would benefit from this form of therapy.

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“…89 However, renin inhibition on top of ARB had no add-on effect on LVH 90 or mortality in HF but was associated with increased adverse effects. Both show favorable results on remodeling and outcome in animal studies, 93,94 but no clinical data are available yet (Box 2). 2), or RASSF1A, which targets Ras.…”

Section: Renin-angiotensin-aldosterone Systemmentioning

confidence: 99%

Targeting Cardiac Hypertrophy

Bisping

Wakula

Poteser³

et al. 2014

Journal of Cardiovascular Pharmacology

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Cardiac hypertrophy is commonly observed in conditions of increased hemodynamic or metabolic stress. This hypertrophy is not compensatory but rather reflects activation of maladaptive cellular processes that promote disease progression. Myocardial hypertrophy serves as a diagnostic and prognostic marker of cardiac remodeling, and underlying regulatory processes have provided effective therapeutic targets to slow disease progression and improve outcome. We review hypertrophic signaling pathways in cardiomyocytes and discuss established and novel targets for pharmacological intervention. New drugs in the pipeline include the third generation aldosterone antagonists (PF-03882845 and BAY94-8862) and biased angiotensin II receptor agonists. Furthermore, different approaches to stimulate cGMP-dependent protective signaling are currently evaluated in clinical trials, including the combination of the vasopeptidase neprilysin inhibitor and an angiotensin receptor blocker (ARNi). In an overview on cardiomyocyte hypertrophic signaling, we also highlight emerging experimental treatment concepts such as inhibition of Ca-mediated transcriptional regulation, adeno-associated viruses for sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a), PI3 kinase gene transfer and microRNA-based therapy. We conclude that antihypertrophic therapy extends beyond blocking the classical β-adrenergic and renin-angiotensin-aldosterone system-dependent signaling cascades, although new therapies require clinical validation regarding outcome.

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Cardiovascular effects of a novel selective Rho kinase inhibitor, 2-(1H-indazole-5-yl)amino-4-methoxy-6-piperazino triazine (DW1865)

Cited by 30 publications

References 33 publications

DL0805-2, a novel indazole derivative, relaxes angiotensin II-induced contractions of rat aortic rings by inhibiting Rho kinase and calcium fluxes

DL0805-2, a novel indazole derivative, relaxes angiotensin II-induced contractions of rat aortic rings by inhibiting Rho kinase and calcium fluxes

Experimental and early investigational drugs for angina pectoris

Targeting Cardiac Hypertrophy

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