SAR407899

SAR407899 is a selective, potent and ATP-competitive ROCK inhibitor, with an IC50 of 135 nM for ROCK-2, and Kis of 36 nM and 41 nM for human and rat ROCK-2, respectively.

In Vitro:SAR407899 is a potent and ATP-competitive ROCK inhibitor, with Kis of 36 nM and 41 nM for human and rat ROCK-2, respectively. SAR407899 inhibits ROCK-2 better than ROCK-1, with IC50s of 102 ± 19 nM and 276 ± 26 nM, respectively, in the presence of 40 μM ATP. SAR407899 also less potently inhibits PKC-Δ and MSK-1, with IC50s of 5.4 and 3.1 μM, respectively. SAR407899 (0.1, 0.3, 1.0, and 3.0 μM) specifically inhibits the ROCK-mediated phosphorylation of MYPTT696 in HeLa cells stimulated with PHEN, and shows such effects at 1 μM and 10 μM in primary rat aortic smooth muscle cells. SAR407899 (3 μM) completely blocks thrombin-induced shrinkage of human umbilical vein endothelial cells (HUVECs) and stress fiber formation. SAR407899 concentration-dependently inhibits 5-bromodeoxyuridine incorporation into the cells with an IC50 of 5.0 ± 1.3 μM. SAR407899 also effectively inhibits THP-1 migration with an IC50 of 2.5 ± 1.0 μM. SAR407899 shows a potent vasorelaxant activity in a broad variety of isolated arteries taken from different vascular beds and species, with a range of IC50 values between 122 and 280 nM[1]. SAR407899 dose-dependently relaxes the phenylephrine pre-contracted smooth muscle, with IC50s of 0.07 and 0.05 μM, respectively[2].

In Vivo:SAR407899 (3 mg/kg, i.v.) inhibits ROCK-mediated phosphorylation of MYPTT696 in thoracic aorta of spontaneously hypertensive rats (SHRs). SAR407899 (0.01-0.30 mg/kg, i.v.) efficiently reduces pressor responses to vasoconstrictor agents in rats. SAR407899 (1, 3, 10, and 30 mg/kg, p.o.) dose dependently lowers blood pressure in hypertensive SHRs[1]. SAR407899 (1-3 mg/kg, i.v. or 3, 10 mg/kg, p.o.) increases the length of the penis in healthy rabbits. SAR407899 (3-10 mg/kg, p.o.) also dose-dependently increases penile length in diabetic rabbits[2].

References:
[1]. Löhn M, et al. Pharmacological characterization of SAR407899, a novel rho-kinase inhibitor. Hypertension. 2009 Sep;54(3):676-83. [2]. Guagnini F, et al. Erectile properties of the Rho-kinase inhibitor SAR407899 in diabetic animals and human isolated corpora cavernosa. J Transl Med. 2012 Mar 23;10:59.

Pharmacological characterization of SAR407899, a novel rho-kinase inhibitor.[Pubmed:19597037]

Hypertension. 2009 Sep;54(3):676-83.

Recent advances in basic and clinical research have identified Rho kinase as an important target potentially implicated in a variety of cardiovascular diseases. Rho kinase is a downstream mediator of RhoA that leads to stress fiber formation, membrane ruffling, smooth muscle contraction, and cell motility. Increased Rho-kinase activity is associated with vasoconstriction and elevated blood pressure. We identified a novel inhibitor of Rho kinase (SAR407899) and characterized its effects in biochemical, cellular, tissue-based, and in vivo assays. SAR407899 is an ATP-competitive Rho-kinase inhibitor, equipotent against human and rat-derived Rho-kinase 2 with inhibition constant values of 36 nM and 41 nM, respectively. It is highly selective in panel of 117 receptor and enzyme targets. SAR407899 is approximately 8-fold more active than fasudil. In vitro, SAR407899 demonstrated concentration-dependent inhibition of Rho-kinase-mediated phosphorylation of myosin phosphatase, thrombin-induced stress fiber formation, platelet-derived growth factor-induced proliferation, and monocyte chemotactic protein-1-stimulated chemotaxis. SAR407899 potently (mean IC(50) values: 122 to 280 nM) and species-independently relaxed precontracted isolated arteries of different species and different vascular beds. In vivo, over the dose range 3 to 30 mg/kg PO, SAR407899 lowered blood pressure in a variety of rodent models of arterial hypertension. The antihypertensive effect of SAR407899 was superior to that of fasudil and Y-27632. In conclusion, SAR407899 is a novel and potent selective Rho-kinase inhibitor with promising antihypertensive activity.

End-organ protection in hypertension by the novel and selective Rho-kinase inhibitor, SAR407899.[Pubmed:25632317]

World J Cardiol. 2015 Jan 26;7(1):31-42.

AIM: To compare the therapeutic efficacy of SAR407899 with the current standard treatment for hypertension [an angiotensin converting enzyme (ACE)-inhibitor and a calcium channel blocker] and compare the frequency and severity of the hypertension-related end-organ damage. METHODS: Long-term pharmacological characte-rization of SAR407899 has been performed in two animal models of hypertension, of which one is sensitive to ACE-inhibition (LNAME) and the other is insensitive [deoxycorticosterone acetate (DOCA)]. SAR407899 efficiently lowered high blood pressure and significantly reduced late-stage end organ damage as indicated by improved heart, kidney and endothelial function and reduced heart and kidney fibrosis in both models of chronic hypertension. RESULTS: Long term treatment with SAR407899 has been well tolerated and dose-dependently reduced elevated blood pressure in both models with no signs of tachyphylaxia. Blood pressure lowering effects and protective effects on hypertension related end organ damage of SAR407899 were superior to ramipril and amlodipine in the DOCA rat. Typical end-organ damage was significantly reduced in the SAR407899-treated animals. Chronic administration of SAR407899 significantly reduced albuminuria in both models. The beneficial effect of SAR407899 was associated with a reduction in leukocyte/macrophage tissue infiltration. The overall protective effect of SAR407899 was superior or comparable to that of ACE-inhibition or calcium channel blockade. Chronic application of SAR407899 protects against hypertension and hypertension-induced end organ damage, regardless of the pathophysiological mechanism of hypertension. CONCLUSION: Rho-kinases-inhibition by the SAR407899 represents a new therapeutic option for the treatment of hypertension and its complications.

The Rho kinase inhibitor SAR407899 potently inhibits endothelin-1-induced constriction of renal resistance arteries.[Pubmed:22388233]

J Hypertens. 2012 May;30(5):980-9.

OBJECTIVES: Increased renal vascular resistance contributes to the pathogenesis of hypertension. The new Rho kinase (ROCK) inhibitor SAR407899 more potently lowers arterial pressure than the commercially available ROCK inhibitor Y27623. We tested whether ROCK inhibition more effectively reduced agonist-induced vasoconstriction in renal than in nonrenal resistance arteries and if SAR407899 more potently inhibits agonist-induced vasoconstriction than Y27632. METHODS: The effects of the ROCK inhibitors on endothelin-1 (ET-1) induced vasoconstriction were investigated in isolated renal and coronary arteries from lean, normotensive Dark Agouti and obese, type 2 diabetic Zucker diabetic fatty (ZDF) rats as well as in isolated human resistance arteries from the kidney and thymus. Vascular ROCK mRNA abundance was studied by real-time PCR (RT-PCR). RESULTS: ET-1-induced constriction depended more on ROCK in rat and human renal resistance arteries than in rat coronary or human thymic arteries, respectively. SAR407899 was more effective than Y27632 in reducing ET-1-induced vasoconstriction in ZDF rat renal resistance arteries. Maximum ET-1-induced vasoconstriction in SAR407899-treated and Y27632-treated human renal resistance arteries was 23 +/- 5 and 48 +/- 6% of control values, respectively. Transcripts of both ROCK isoforms were detected in rat and human renal resistance arteries. In human thymic arteries, only the ROCK2 transcript was found. CONCLUSION: ET-1-induced vasoconstriction is more ROCK-dependent in renal than in nonrenal resistance arteries. SAR407899 causes a greater inhibition of ET-1-induced vasoconstriction in renal resistance arteries from ZDF rats and patients than Y27632. The greater efficacy in renal vessels may contribute to the higher antihypertensive potency of SAR407899 compared with Y27632.

Erectile properties of the Rho-kinase inhibitor SAR407899 in diabetic animals and human isolated corpora cavernosa.[Pubmed:22444253]

J Transl Med. 2012 Mar 23;10:59.

BACKGROUND: RhoA-Rho kinase complex contributes to keep the cavernosus smooth muscle contracted and its inhibition is considered a potential strategy for the therapy of erectile dysfunction (ED). METHODS: We compared the effects of SAR407899, the Rho-kinase inhibitor Y-27632 and the PDE5 inhibitor sildenafil for their ability to relax corpus cavernosum strips contracted with phenylephrine in healthy and diabetic animals. Strips were obtained from WKY, spontaneous hypertensive (SHR), control CD, and diabetic CD rats, humans, control and diabetic rabbits. Diabetes was induced by streptozotocin or alloxan injection. In vivo penile erection (length) induced by drugs was measured in conscious rabbits. RESULTS: SAR407899 dose-dependently relaxed the pre-contracted corpora cavernosa in all species, with similar potency and efficacy in healthy vs diabetic rats, WKY vs SHR rats, healthy vs diabetic rabbits (IC(50) range from 0.05 to 0.29 muM, Emax range 89 to 97%). In the presence of the NO-synthase (NOS) inhibitor, L-NAME, the SAR407899 response did not decrease in any of the species or experimental conditions. The effect was confirmed in human strips where sildenafil was significantly less potent and effective, with IC50 respectively 0.13 and 0.51 muM; Emax 92 and 43%. Unlike SAR407899, the potency and efficacy of sildenafil and Y27632 were significantly reduced by diabetes and L-NAME. In vivo, SAR407899 dose-dependently induced rabbit penile erection, with greater potency and longer duration of action than sildenafil. Sildenafil, but not SAR407899, was less effective in alloxan-induced diabetes. CONCLUSION: The induction of penile erection by SAR407899, unlike that by sildenafil, is largely independent of e-NO activity. This suggests its use in erectile dysfunction for diabetic and hypertensive patients where e-NO activity is impaired.

SAR407899 is a selective, potent and ATP-competitive ROCK inhibitor, with an IC50 of 135 nM for ROCK-2, and Kis of 36 nM and 41 nM for human and rat ROCK-2, respectively.

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