Delving into the Latest Updates on SAR-407899 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [1]

Target

ROCK

Action

inhibitors

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/Sequence

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

EUCTR2009-015066-61-AT

/ Not yet recruitingNot Applicable

Efficacy and safety of SAR407899A in patients with painful diabetic neuropathy. A 28-day, randomized, double-blind, placebo-controlled, parallel-group study.

Start Date26 Nov 2009

Sponsor / Collaborator

Sanofi-Aventis Recherche et Développement SA

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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15

Literatures (Medical) associated with SAR-407899

01 Nov 2024·Journal of Computational Biophysics and Chemistry

Molecular Docking, Quantum Mechanics and Molecular Dynamics Simulation of Anti-CAD Drugs Against High-Risk Xanthine Dehydrogenase Variants Associated with Oxidative Stress Pathways

Author: Ahmed, Shiek S. S. J. ; Ahmad, Sheikh F. ; Emran, Talha Bin ; Janakiraman, V. ; Attia, Sabry M. ; Sudhan, M.

Xanthine dehydrogenase (XDH) contributes significantly to generating reactive oxygen species in coronary artery disease (CAD). XDH has been proposed as a therapeutic target, but its genetic variants could affect protein structure and drug response. We aimed to assess protein structure modification occur due to genetic variants and to screen 215 CAD drugs for their utility in personalized CAD treatment against the XDH variants. A series of computational methods were implemented to identify pathogenic variants that cause XDH structure instability localized at the con served regions contributing to functional significance. Then, the XDH structures with the pathogenic variants were modeled using two different approaches to select the best models for docking with the CAD drugs. Finally, the stability of the docked complexes and their ability to transfer electrons were evaluated using molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculation. Among 751 variants examined; R149C and Q919R showed high pathogenicity, localized in conserved regions could alter protein structure and function. Further, docking of CAD drugs against XDH (native, R149C and Q919R) showed vericiguat with higher affinity, ranging from −7.95 kcal/mol to −10.41 kcal/mol, than the well-known XDH inhibitor (febuxostat, −5.73 kcal/mol to −8.35 kcal/mol). This indicates that vericiguat will be effective in CAD treatment, regardless of the XDH variants. Additionally, MD simulation and QM/MM confirmed vericiguat stability and electron transfer ability to form hydrogen bonds with the XDH protein. In conclusion, vericiguat will be beneficial for the personalized treatment of CAD by inhibiting XDH variants. Additional clinical studies are necessary to confirm our findings.

01 May 2024·Biomedicine & Pharmacotherapy

“Keep on ROCKIn”: Repurposed ROCK inhibitors to boost corneal endothelial regeneration

Article

Author: Van den Bogerd, Bert ; Kotulova, Jana ; Le Compte, Maxim ; De La Hoz, Edgar Cardenas ; Vercammen, Hendrik ; Koppen, Carina ; Deben, Christophe ; Ondra, Martin ; Witters, Charissa ; Ní Dhubhghaill, Sorcha ; Hajdúch, Marián ; Jecmenova, Katerina

The global shortage of corneal endothelial graft tissue necessitates the exploration of alternative therapeutic strategies. Rho-associated protein kinase inhibitors (ROCKi), recognized for their regenerative potential in cardiology, oncology, and neurology, have shown promise in corneal endothelial regeneration. This study investigates the repurposing potential of additional ROCKi compounds. Through screening a self-assembled library of ROCKi on B4G12 corneal endothelial cells, we evaluated their dose-dependent effects on proliferation, migration, and toxicity using live-cell imaging. Nine ROCKi candidates significantly enhanced B4G12 proliferation compared to the basal growth rate. These candidates were further assessed for their potential to accelerate wound closure as another indicator for tissue regeneration capacity, with most demonstrating notable efficacy. To assess the potential impact of candidate ROCKi on key corneal endothelial cell markers related to cell proliferation, leaky tight junctions and ion efflux capacity, we analyzed the protein expression of cyclin E1, CDK2, p16, ZO-1 and Na⁺/K⁺-ATPase, respectively. Immunocytochemistry and western blot analysis confirmed the preservation of corneal endothelial markers post-treatment with ROCKi hits. However, notable cytoplasm enlargement and nuclear fragmentation were detected after the treatment with SR-3677 and Thiazovivin, indicating possible cellular stress. In compared parameters, Chroman-1 at a concentration of 10 nM outperformed other ROCKi, requiring significantly 1000-fold lower effective concentration than established ROCKi Y-27632 and Fasudil. Altogether, this study underscores the potential of repurposing ROCKi for treating corneal endothelial dysfunctions, offering a viable alternative to conventional grafting methods, and highlights Chroman-1 as a promising candidate structure for hit-to-lead development.

01 Jan 2021·Indian Journal of Biochemistry and Biophysics

Targeting ROCK2 isoform with its widely used inhibitors for faster post-stroke recovery

Author: Swarup, Vishnu ; Gupta, Deepika ; Appunni, Sandeep ; Rubens, Muni ; Singh, Himanshu Narayan ; Singh, Anjani Kumar

Recovery after ischemic stroke is slow and highly variable.Activated ROCK (Rho-associated coiled-coil kinase) pathway hampers recovery of impaired neurons.Though inhibiting ROCK pathway has shown therapeutic effects in vitro, the selectivity of most of the ROCK inhibitors is still not investigated.Present study aims to investigate the binding affinity in silico of nine widely used ROCK inhibitors with brain-specific ROCK2 isoform.Three-dimensional structures of ROCK2 and eight drugs were taken from Protein Data Bank and PubChem Chem. Compound Database, resp., whereas, FSD-C10 structure was generated based on Xin et al., 2015.In docking, ROCK2 was set to be rigid and drugs were free to rotate.All simulations were carried out using Autodock-4.2.This study demonstrated strong complexation between all ligands and ROCK2.All ROCK inhibitors, except FSD-C10, were able to bind to ROCK2 more strongly [Binding constant (Ka) between 2.6 - 36.7 x 10⁵ M^-1] than fasudil (Ka = 2.5 x 10⁵ M^-1).SLx-2119 (KD-025) had the highest binding constant (Ka = 36.7 x 10⁵ M^-1) thus succeeding as a better ROCK2 specific inhibitor.Selectivity of ROCK inhibitors (in silico) towards ROCK2 can be an indicative measure to estimate therapeutic benefits or adverse effects prior to in vitro study.

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	South Korea	Sanofi	12 Oct 2017
Angina, Stable	Phase 2	Sweden	Sanofi	12 Oct 2017
Angina, Stable	Phase 2	United States	Sanofi	12 Oct 2017
Angina, Stable	Phase 2	Netherlands	Sanofi	12 Oct 2017
Mevalonate Kinase Deficiency	Phase 2	South Korea	Sanofi	12 Oct 2017
Mevalonate Kinase Deficiency	Phase 2	Netherlands	Sanofi	12 Oct 2017
Mevalonate Kinase Deficiency	Phase 2	Denmark	Sanofi	12 Oct 2017
Mevalonate Kinase Deficiency	Phase 2	United States	Sanofi	12 Oct 2017
Mevalonate Kinase Deficiency	Phase 2	Sweden	Sanofi	12 Oct 2017
Erectile Dysfunction	Phase 2	France	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)	urahlprwcg(vmfoynwduj) = cuycwjzxqq itwdcppcpa (wecathhayw, cwqeodpgxx - doebdripdj) View more	-	11 Jul 2019
				82Rubidium+SAR407899+13N-ammonia+Regadenoson+Adenosine (SAR407899)	urahlprwcg(vmfoynwduj) = dbiboarvrl itwdcppcpa (wecathhayw, mqweaxtwjj - epvqzzmshe) View more