Case Control Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Cardiol. Jan 26, 2015; 7(1): 31-42
Published online Jan 26, 2015. doi: 10.4330/wjc.v7.i1.31
End-organ protection in hypertension by the novel and selective Rho-kinase inhibitor, SAR407899
Matthias Löhn, Oliver Plettenburg, Aimo Kannt, Markus Kohlmann, Armin Hofmeister, Dieter Kadereit, Peter Monecke, Alexander Schiffer, Anke Schulte, Hartmut Ruetten, Yuri Ivashchenko
Matthias Löhn, Oliver Plettenburg, Aimo Kannt, Markus Kohlmann, Armin Hofmeister, Dieter Kadereit, Peter Monecke, Alexander Schiffer, Anke Schulte, Hartmut Ruetten, Yuri Ivashchenko, Translational Medicine, Sanofi-Aventis, Industriepark Hoechst, 65926 Frankfurt am Main, Germany
Author contributions: Löhn M performed the majority of experiments, designed the study and wrote the manuscript; Plettenburg O, Hofmeister A and Kadereit D designed and synthetized SAR407899; Kannt A performed an initial compound screening; Kohlmann M performed the pharmacokinetics of SAR407899; Monecke P and Schiffer A were involved in structural biology and modeling required for the compound optimization; Schulte A performed the histology; Ruetten H and Ivashchenko Y were also involved in writing and editing the manuscript.
Ethics approval: All animal experiments were performed in accordance with the German law for the protection of animals and current Aventis Laboratory Animal Science and Welfare (LASW) guidelines.
Informed consent: Not applicable.
Conflict-of-interest: There is no conflict-of-interest to disclose. All authors are employees of Sanofi-Aventis Deutschland GmbH.
Data sharing: Technical appendix, statistical code, and dataset available from the corresponding author at Matthias.loehn@sanofi.com. Participants gave informed consent for data sharing. No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Matthias Löhn, Translational Medicine, Sanofi-Aventis, Industriepark Hoechst, 65926 Frankfurt am Main, Germany. matthias.loehn@sanofi.com
Telephone: +49-69-30517118
Received: July 14, 2014
Peer-review started: July 15, 2014
First decision: November 3, 2014
Revised: December 12, 2014
Accepted: December 29, 2014
Article in press: January 4, 2015
Published online: January 26, 2015
Processing time: 190 Days and 22.3 Hours
Abstract

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.

Keywords: Hypertension; End organ damage; Rho-kinase; Angiotensin converting enzyme-inhibition

Core tip: Rho-kinase (ROCK) is considered an important target in cardiovascular diseases, e.g., hypertension and nephropathy. Currently available treatment only moderately alleviates the progression of chronic kidney diseases. We have identified a novel, potent and selective inhibitor of ROCK (SAR407899) and characterized its effects in vivo. The therapeutic efficacy of SAR407899 has been compared to the current standard treatment for hypertension in two animal models of hypertension, one of which is sensitive and the other insensitive (deoxycorticosterone acetate) to angiotensin converting enzyme-inhibition. ROCK-inhibition by SAR407899 may represent a new therapeutic option either as a monotherapy or in combination with existing modern therapeutics for the treatment of hypertension and its complications.