Delving into the Latest Updates on SAR-407899 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [1]

Target

ROCK

Mechanism

ROCK inhibitors(Rho-associated kinases inhibitors)

Therapeutic Areas

Immune System DiseasesNervous System DiseasesCardiovascular Diseases+ [6]

Active Indication-

Inactive Indication

Angina, StableChronic Kidney DiseasesErectile Dysfunction+ [2]

Originator Organization

Sanofi-Aventis U.S. LLC

Active Organization-

Inactive Organization

Sanofi

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC14H16N2O2

InChIKeyIPEXHQGMTHOKQV-UHFFFAOYSA-N

CAS Registry923359-38-0

View All Structures (2)

Primary Objective:
To assess the effects of SAR407899 on coronary vasomotor function using the coronary flow reserve (CFR) in participants with microvascular angina (MVA) and/or persistent stable angina despite angiographically successful percutaneous coronary intervention (PCI).
Secondary Objectives:
To assess the effects of SAR407899 on quality of life using Seattle Angina Questionnaire physical limitation scale (SAQ-PL) in participants with MVA and/or persistent stable angina despite angiographically successful PCI.
To assess the safety of SAR407899 in participants with MVA and/or persistent stable angina despite angiographically successful PCI with a focus on identified risks such as hypotension and orthostatic hypotension.
To assess SAR407899 plasma concentrations in MVA participants and/or persistent stable angina despite angiographically successful PCI.

Start Date12 Oct 2017

Sponsor / Collaborator

Sanofi

NCT01485900 / CompletedPhase 1

A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability and Hemodynamics of Ascending Repeated Oral Doses of SAR407899A in Patients With Moderate Chronic Kidney Disease on Stable Angiotensin Converting Enzyme-inhibitor (ACE-I) Treatment

Primary Objective:
To assess the tolerability and safety of repeated oral ascending doses of SAR407899A in patients with moderate chronic kidney disease (CKD) on stable angiotensin converting enzyme-inhibitor (ACE-I)
Secondary Objectives:
To assess in patients with moderate CKD the effect of concomitant multiple dose of SAR407899A and ACE-Is on office and 24-hr ambulatory blood pressure and heart rate
The effect of repeated multiple doses of SAR407899A on the pharmacodynamic response to ACE-Is (AcSDKP)
The pharmacokinetic profile of repeated oral administration of SAR407899A during co-administration of ACE-Is

Start Date01 Nov 2011

Sponsor / Collaborator

Sanofi

100 Clinical Results associated with SAR-407899

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100 Translational Medicine associated with SAR-407899

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100 Patents (Medical) associated with SAR-407899

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7

Literatures (Medical) associated with SAR-407899

01 Oct 2018·Transplant ImmunologyQ4 · MEDICINE

Screening RhoA/ROCK inhibitors for the ability to prevent chronic rejection of mouse cardiac allografts

Q4 · MEDICINE

Article

Author: Wenhao Chen ; Rafik M. Ghobrial ; Malgorzata Kloc ; Wei Chen ; Xian C. Li ; Song Chen

BACKGROUNDChronic rejection of transplanted organs is a major obstacle in organ transplantation. The main symptoms of chronic rejection are vessel occlusion and tissue fibrosis. Macrophages play a crucial role in chronic rejection. We showed previously that RhoA deletion or RhoA/Rock inhibition using Y27632 inhibitor reorganizes macrophage actin cytoskeleton, prevents macrophage movement to the cardiac allografts, and abrogates chronic rejection in rodent models. Although besides Y27632 there are other RhoA/ROCK inhibitors available commercially, their efficacy in inhibition of chronic rejection remains unknown.METHODSWe screened four RhoA/Rock inhibitors for their ability to inhibit chronic rejection of BALB/c [H-2d] mouse cardiac allografts heterotopically transplanted into C57BL/6 [H-2b] recipients. We also tested the effect of inhibitors on macrophages in vitro.RESULTSWe found that out of four tested compounds, the Fasudil and Azaindole, inhibited vessel occlusion, tissue fibrosis, decreased M2 macrophage infiltration and abrogated chronic rejection of mouse cardiac allografts. The remaining inhibitors, SAR-407899 and SLX-2119, decreased only tissue fibrosis, and were ineffective or only slightly effective in inhibiting vessel occlusion. We also found that Azaindole and Fasudil affected actin cytoskeleton and protein expression in mouse peritoneal macrophages CONCLUSION: Results of these studies might help in development of anti-chronic rejection therapy for clinical use.

01 Jan 2015·World Journal of Cardiology

End-organ protection in hypertension by the novel and selective Rho-kinase inhibitor, SAR407899

Article

Author: Löhn, Matthias ; Hofmeister, Armin ; Kadereit, Dieter ; Plettenburg, Oliver ; Ruetten, Hartmut ; Kannt, Aimo ; Ivashchenko, Yuri ; Kohlmann, Markus ; Schulte, Anke ; Schiffer, Alexander ; Monecke, Peter

AIMTo 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.METHODSLong-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.RESULTSLong 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.CONCLUSIONRho-kinases-inhibition by the SAR407899 represents a new therapeutic option for the treatment of hypertension and its complications.

01 Dec 2012·Journal of Translational MedicineQ2 · MEDICINE

Erectile properties of the Rho-kinase inhibitor SAR407899 in diabetic animals and human isolated corpora cavernosa

Q2 · MEDICINE

ArticleOA

Author: Fabio Guagnini ; Tiziano Croci ; Marco Grasso ; Mara Ferazzini ; Salvatore Blanco

BACKGROUNDRhoA-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).METHODSWe 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.RESULTSSAR407899 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 μM, 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 μM; 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.CONCLUSIONThe 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.

100 Deals associated with SAR-407899

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Angina, Stable	Phase 2	KR	Sanofi	12 Oct 2017
Angina, Stable	Phase 2	SE	Sanofi	12 Oct 2017
Angina, Stable	Phase 2	US	Sanofi	12 Oct 2017
Angina, Stable	Phase 2	NL	Sanofi	12 Oct 2017
Mevalonate Kinase Deficiency	Phase 2	KR	Sanofi	12 Oct 2017
Mevalonate Kinase Deficiency	Phase 2	NL	Sanofi	12 Oct 2017
Mevalonate Kinase Deficiency	Phase 2	DK	Sanofi	12 Oct 2017
Mevalonate Kinase Deficiency	Phase 2	US	Sanofi	12 Oct 2017
Mevalonate Kinase Deficiency	Phase 2	SE	Sanofi	12 Oct 2017
Erectile Dysfunction	Phase 2	FR	Sanofi	01 May 2009

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03236311 (CTgov)	Phase 2	Microvascular Angina \| Mevalonate Kinase Deficiency \| Angina, Stable	10	82Rubidium+13N-ammonia+Regadenoson+Adenosine (Placebo)	kofcazzmrm(ibcdobwgwd) = mtcrcieayf fxcskybefk (cwcuglrhvb, kmyodreuce - fqvwxgdxxh) View more	-	11 Jul 2019
				82Rubidium+SAR407899+13N-ammonia+Regadenoson+Adenosine (SAR407899)	kofcazzmrm(ibcdobwgwd) = qldksufbbd fxcskybefk (cwcuglrhvb, bkbjaakcqa - afckmkpmlx) View more