Analysis of Pulmonary Vasodilator Responses to SB-772077-B [4-(7-((3-Amino-1-pyrrolidinyl)carbonyl)-1-ethyl-1H-imidazo(4,5-c)pyridin-2-yl)-1,2,5-oxadiazol-3-amine], a Novel Aminofurazan-Based Rho Kinase Inhibitor

Dhaliwal, Jagjit Singh; Badejo, Adeleke M.; Casey, David B.; Murthy, Subramanyam N.; Kadowitz, Philip J.

doi:10.1124/jpet.109.151449

Cited by 22 publications

(25 citation statements)

References 34 publications

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“…Recent studies have shown that Rho/ROCK pathway is increased in pulmonary hypertension patients. 183,184 Numerous studies using fasudil 137,185–197 and other ROCK inhibitors 117,196,198 in different experimental models have shown that ROCK is a critical contributor to pulmonary hypertension. ROCK inhibitors can reduce pulmonary arterial pressure, pulmonary vascular resistance and remodeling by reducing pulmonary vasoconstriction, 185–187,193 improving endothelial function, 188,191,193 decreasing smooth muscle cell proliferation and migration, 196,199,200 increasing smooth muscle cell apoptosis, 193,198 increasing myofibroblast apoptosis and reducing fibrosis, 194 decreasing vascular oxidative stress and inflammation.…”

Section: Rock In Cardiovascular Diseasesmentioning

confidence: 99%

Rho Kinases in Cardiovascular Physiology and Pathophysiology

Shi

Wei

2013

Journal of Cardiovascular Pharmacology

137

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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.

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Section: Rock In Cardiovascular Diseasesmentioning

confidence: 99%

Rho Kinases in Cardiovascular Physiology and Pathophysiology

Shi

Wei

2013

Journal of Cardiovascular Pharmacology

137

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“…117 This novel aminofurazan-based ROCK inhibitor had a beneficial effect in monocrotaline-inducedPH, and animals treated with SB-772077-Bfor 21 days had significantly lower PAPs compared with untreated control rats. 117 The effect of SB-772077-B in monocrotaline-treated rats with PH is shown in figure 3 where it can be seen that the ROCK inhibitor did not have a selective vasodilator effect in the pulmonary vascular bed. The comparison of responses to SB-772077-B in control and monocrotaline-treated animals can provide an estimate of the amount of reversible and fixed vasoconstrictor tone in the pulmonary vascular bed in animals with PH.…”

Section: Treatment Of Pulmonary Hypertensionmentioning

confidence: 92%

New Approaches to the Treatment of Pulmonary Hypertension

Murthy¹,

Nossaman²,

Kadowitz³

2010

Cardiology in Review

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Pulmonary hypertension (PH) is a severe, life-threatening disease for which there are no effective curative therapies. A diverse group of agents such as prostacyclins, endothelin antagonists, phosphodiesterase inhibitors, calcium channel blockers, diuretics, inotropic agents, and anticoagulants are used to treat PH; however, none of these agents have a marked effect upon survival. Among the new agents that show promise in the treatment of PH are Rho-kinase inhibitors and soluble guanylate cyclase stimulators. Although these new classes of agents have beneficial effects in experimental animal models and clinical studies, they are not selective in their actions on the pulmonary vascular bed. This manuscript reviews the actions of Rho-kinase inhibitors and soluble guanylate cyclase stimulators on the pulmonary vascular bed. It is our hypothesis that these new agents may be more effective than current therapies in the treatment of PH. Moreover, new methods in the delivery of these agents to the lung need to be developed so that their main effects will be exerted in the pulmonary vascular bed and their systemic effects can be minimized or avoided. KeywordsRhoA/Rho-kinase pathway; smooth muscle; vascular; pulmonary hypertension; inhibitors/ pharmacology; cardiovascular diseases; Fasudil; HA-1077; Y-27632; SB-772077-B; soluble guanylate cyclase; riociguat Pulmonary arterial hypertension (PH) is a rare disorder that without treatment is progressive and often fatal within 3 years. [1][2][3][4] The most common symptom at presentation is dyspnea with other complaints including fatigue, chest pain, syncope, leg edema, and palpitations. [1][2][3][4] PH is also associated with other conditions or risk factors (e.g., collagen vascular diseases, portal hypertension, human immunodeficiency virus infection, drug use, toxins, dietary products, persistent fetal circulation, chronic thromboembolism, cancer, and diastolic heart failure, 5-17 and the incidence of this disorder is increasing.A national registry was begun in 1911 to collect medical data from 32 centers in patients diagnosed by uniform criteria as having PH [18]. One hundred eighty seven patients were Corresponding Author: Philip J. Kadowitz, Ph.D., Department of Pharmacology, Tulane University Medical Center, 1430 Tulane Avenue, SL83, New Orleans, Louisiana 70112-2699 USA, 504 988-2634, 504 988-5283, pkadowi@tulane.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. entered into the registry with a mean age of 37 years (1-81 yrs) and with a female to male ratio of 1:1.7. 18 Pulmonary function studies showed mild restrict...

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“…It has been reported that intravenous injection of several chemically different ROCK inhibitors reduces systemic and pulmonary arterial pressures even under resting conditions. [161][162][163][164] These results suggest that ROCK plays a physiological role in the maintenance of baseline vasoconstrictor tone in the pulmonary and systemic vascular beds and is involved in the development of PH. …”

mentioning

confidence: 84%

2015 ATVB Plenary Lecture

Shimokawa

Satoh

2015

ATVB

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Abstract-Rho-kinase (ROCKs) is an important downstream effector of the small GTP-binding protein Ras homolog gene family member A. There are 2 isoforms of ROCK, ROCK1 and ROCK2, and they have different functions in several vascular components. The Ras homolog gene family member A/ROCK pathway plays an important role in various fundamental cellular functions, including contraction, motility, proliferation, and apoptosis, whereas its excessive activity is involved in the pathogenesis of cardiovascular diseases. For the past 20 years, a series of translational research studies have demonstrated the important roles of ROCK in the pathogenesis of cardiovascular diseases. At the molecular and cellular levels, ROCK upregulates several molecules related to inflammation, thrombosis, and fibrosis. In animal experiments, ROCK plays an important role in the pathogenesis of vasospasm, arteriosclerosis, hypertension, pulmonary hypertension, and heart failure. Finally, at the human level, ROCK is substantially involved in the pathogenesis of coronary vasospasm, angina pectoris, hypertension, pulmonary hypertension, and heart failure. Furthermore, ROCK activity in circulating leukocytes is a useful biomarker for the assessment of disease severity and therapeutic responses in vasospastic angina, heart failure, and pulmonary hypertension. In addition to fasudil, many other ROCK inhibitors are currently under development for various indications. Thus, the ROCK pathway is an important novel therapeutic target in cardiovascular medicine. ). [20][21][22][23] Both endothelial NO production and NO-mediated signaling in VSMC are targets and effectors of the RhoA/ROCK pathway. 1,24,25 In EC, the RhoA/ROCK pathway negatively regulates NO production, although in VSMC, the pathway enhances MLC phosphorylation through inhibition of MYPT-1 of MLCP and promotes VSMC contraction ( Figure 1). 26ROCK is a serine/threonine kinase, which is encoded by 2 different genes. In humans, ROCK1 (ROCKβ) and ROCK2 (ROCKα) genes are located separately on chromosome 18 and 2, respectively. 27,28 ROCK consists of 3 major domains, including a kinase domain, a coiled-coil domain that include Rhobinding domain and a putative pleckstrin homology domain ( Figure 3). 4 ROCK activity is enhanced by binding of GTPbound active form of RhoA.28 Several ROCK substrates have been identified 27 and phosphorylation of ROCK-mediated substrate causes actin filament formation, organization, and cytoskeleton rearrangement (Figure 1). 29 Nowadays, many ROCK inhibitors, such as fasudil 30 and Y-27632, 31 have been developed and they inhibit ROCK activity in a competitive manner with ATP at the Rho-binding site. 32 Among them, hydroxyfasudil, a major active metabolite of fasudil, exerts a more specific inhibitory effect on ROCK. 33,34 Roles of ROCK in ECThe RhoA/ROCK pathway is critically involved in actin dynamics. 35 Cyclic strain stimulates RhoA activation and enhances cell contractility. Mechanical activation of the RhoA/ROCK system makes cells more sensitive to external stimuli...

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Analysis of Pulmonary Vasodilator Responses to SB-772077-B [4-(7-((3-Amino-1-pyrrolidinyl)carbonyl)-1-ethyl-1H-imidazo(4,5-c)pyridin-2-yl)-1,2,5-oxadiazol-3-amine], a Novel Aminofurazan-Based Rho Kinase Inhibitor

Cited by 22 publications

References 34 publications

Rho Kinases in Cardiovascular Physiology and Pathophysiology

Rho Kinases in Cardiovascular Physiology and Pathophysiology

New Approaches to the Treatment of Pulmonary Hypertension

2015 ATVB Plenary Lecture

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