Cardiovascular effects of a novel potent and highly selective azaindole‐based inhibitor of Rho‐kinase

Kast, Raimund; Schirok, Hartmut; Figueroa‐Pérez, Santiago; Mittendorf, Joachim; Gnoth, Mark Jean; Apeler, Heiner; Lenz, J; Fränz, J; Knorr, Andreas; Hütter, Joachim; Lobell, Mario; Zimmermann, Katharina; Münter, Klaus; Augstein, K H; Ehmke, Heimo; Stasch, Johannes‐Peter

doi:10.1038/sj.bjp.0707484

Cited by 60 publications

(45 citation statements)

References 27 publications

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“…Azaindole-1 was prepared daily in transcutol-based vehicle as described [28] and rats were treated by oral gavage at the dose of 10 mg per kg body weight per day. The placebo group received only vehicle.…”

Section: Experimental Designmentioning

confidence: 99%

“…The placebo group received only vehicle. The dose of azaindole-1 was selected based on literature [28] and our own pilot experiments (data not shown). The right ventricular systolic pressure (RVSP) and heart rate were monitored online with an implanted radio-telemetry system (Dataquest A.R.T.…”

Section: Experimental Designmentioning

confidence: 99%

“…Mice exposed to chronic hypoxia were treated daily with azaindole-1 (30 mg per kg body weight per day) or placebo from 21 to 35 days. As mentioned, the dose of azaindole-1 was selected based on literature [28] and our own pilot experiments (data not shown) and prepared daily for oral application. Control mice remained under normoxia (21% O 2 ).…”

Section: Chronic Treatment Studymentioning

confidence: 99%

“…The ROCK inhibitors show beneficial effects on rodent models of PH; however, discrepancy in their efficacy has also been observed depending on the dose, route of administration and animal model [9]. Recently, a highly selective and orally active azaindole-based ROCK inhibitor has been reported [28,29]. This novel ROCK inhibitor, azaindole-1, functions in an ATP-competitive manner with activity in the low nanomolar range (half maximal inhibitory concentration (IC 50 ) of 0.6 nM and 1.1 nM for human ROCK1 and ROCK2, respectively).…”

mentioning

confidence: 99%

“…This novel ROCK inhibitor, azaindole-1, functions in an ATP-competitive manner with activity in the low nanomolar range (half maximal inhibitory concentration (IC 50 ) of 0.6 nM and 1.1 nM for human ROCK1 and ROCK2, respectively). Moreover, oral administration of azaindole-1 induces a dose-dependent decrease in blood pressure without inducing a significant reflex increase in heart rate of normotensive and spontaneously hypertensive rats [28]. However, the therapeutic potential of azaindole-1 in animal models of PH has not yet been explored.…”

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confidence: 99%

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Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension

Dahal¹,

Kosanovic²,

Pk³

et al. 2010

Eur Respir J

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An accumulating body of evidence incriminates Rho kinase (ROCK) in the pathogenesis of pulmonary hypertension (PH). The therapeutic efficacy of azaindole-1, a novel highly selective and orally active ROCK inhibitor, has not yet been investigated in PH.This study aimed to investigate the effects of azaindole-1 on 1) acute hypoxic pulmonary vasoconstriction (HPV), 2) proliferation of pulmonary arterial smooth muscle cells (PASMCs) and 3) animal models of PH.Azaindole-1 significantly inhibited HPV in isolated, ventilated and buffer-perfused murine lungs and proliferation of primary rat PASMCs in vitro. Azaindole-1 was administered orally from 21 to 35 days after monocrotaline (MCT) injection in rats and hypoxic exposure in mice. Azaindole-1 (10 and 30 mg per kg body weight per day in rats and mice, respectively) significantly improved haemodynamics and right ventricular hypertrophy. Moreover, the medial wall thickness and muscularisation of peripheral pulmonary arteries were ameliorated. Azaindole-1 treatment resulted in a decreased immunoreactivity for phospho-myosin phosphatase target subunit 1 and proliferating cell nuclear antigen in pulmonary vessels of MCT-injected rats, suggesting an impaired ROCK activity and reduced proliferating cells.Azaindole-1 provided therapeutic benefit in experimental PH, and this may be attributable to its potent vasorelaxant and antiproliferative effects. Azaindole-1 may offer a useful approach for treatment of PH.KEYWORDS: Azaindole-1, hypoxia, monocrotaline, pulmonary hypertension, Rho kinase P ulmonary arterial hypertension (PAH) is a chronic fatal disease characterised by sustained elevation of pulmonary artery pressure and reduced exercise tolerance. As a consequence, the right ventricular afterload increases and culminates in right ventricular failure. PAH has a complex pulmonary vascular pathophysiology, including vasoconstriction, vascular remodelling and in situ thrombosis. The progressive vascular remodelling, the hallmark of PAH pathology, is attributable to abnormalities in vascular cells, such as increased proliferation and resistance to apoptosis [1][2][3]. However, the precise molecular mechanism is incompletely understood, and so a therapeutic approach for curing this disease is currently sought after.The small GTPase RhoA is one of the members of the Rho protein family that regulate cellular functions such as contraction, motility, proliferation and apoptosis, and Rho kinases (ROCKs) are the best characterised downstream targets for RhoA [4]. Two isoforms of the serine/threonine kinase ROCK have been identified: . ROCKs are ubiquitously expressed in tissues including vasculature and heart. Owing to its role in key cell functions, hyperactive ROCK signalling results in cardiovascular disorders associated with sustained abnormal vasoconstriction and promotion of vascular remodelling [8,9]. Studies on animal models of pulmonary hypertension (PH), such as chronic hypoxia-, monocrotaline (MCT)-, vascular endothelial growth factor receptor inhibition and chron...

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Section: Experimental Designmentioning

confidence: 99%

Section: Experimental Designmentioning

confidence: 99%

Section: Chronic Treatment Studymentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension

Dahal¹,

Kosanovic²,

Pk³

et al. 2010

Eur Respir J

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SelectiveROCK2 inhibition in focal cerebral ischemia

Lee

Zheng

Bornstädt

et al. 2013

Ann Clin Transl Neurol

109

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Objective Rho-associated kinase (ROCK) is a key regulator of numerous processes in multiple cell types relevant in stroke pathophysiology. ROCK inhibitors have improved outcome in experimental models of acute ischemic or hemorrhagic stroke. However, the relevant ROCK isoform (ROCK1 or ROCK2) in acute stroke is not known. Methods We characterized the pharmacodynamic and pharmacokinetic profile, and tested the efficacy and safety of a novel selective ROCK2 inhibitor KD025 (formerly SLx-2119) in focal cerebral ischemia models in mice. Results KD025 dose-dependently reduced infarct volume after transient middle cerebral artery occlusion. The therapeutic window was at least 3 hours from stroke onset, and the efficacy was sustained for at least 4 weeks. KD025 was at least as efficacious in aged, diabetic or female mice, as in normal adult males. Concurrent treatment with atorvastatin was safe, but not additive or synergistic. KD025 was also safe in a permanent ischemia model, albeit with diminished efficacy. As one mechanism of protection, KD025 improved cortical perfusion in a distal middle cerebral artery occlusion model, implicating enhanced collateral flow. Unlike isoform-nonselective ROCK inhibitors, KD025 did not cause significant hypotension, a dose-limiting side effect in acute ischemic stroke. Interpretation Altogether, these data show that KD025 is efficacious and safe in acute focal cerebral ischemia in mice, implicating ROCK2 as the relevant isoform in acute ischemic stroke. Data suggest that selective ROCK2 inhibition has a favorable safety profile to facilitate clinical translation.

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Design and Synthesis of Potent and Selective Azaindole‐Based Rho Kinase (ROCK) Inhibitors

et al. 2008

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Rho kinase plays a pivotal role in several cellular processes such as vasoregulation, making it a suitable target for the treatment of hypertension and related disorders. We discovered a new compound class of Rho kinase (ROCK) inhibitors containing a 7-azaindole hinge-binding scaffold tethered to an aminopyrimidine core. Herein we describe the structure-activity relationships elucidated through biochemical and functional assays. The introduction of suitable substituents at the 3-position of the bicyclic moiety led to an increase in activity, which was required to design compounds with favorable pharmacokinetic profile. Azaindole 32 was identified as a highly selective and orally available ROCK inhibitor able to cause a sustained blood pressure reduction in vivo.

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Cardiovascular effects of a novel potent and highly selective azaindole‐based inhibitor of Rho‐kinase

Cited by 60 publications

References 27 publications

Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension

Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension

SelectiveROCK2 inhibition in focal cerebral ischemia

Design and Synthesis of Potent and Selective Azaindole‐Based Rho Kinase (ROCK) Inhibitors

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