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Table of Contents
Vol. 90, No. 3-4, 2012
Issue release date: October 2012
Section title: Original Paper
Pharmacology 2012;90:193–204
(DOI:10.1159/000339861)

Characterization of New Organic Nitrate Hybrid Drugs Covalently Bound to Valsartan and Cilostazol

Knorr M.a,b · Hausding M.a,b · Schulz E.a · Oelze M.a · Rümmler R.a · Schuff A.a · Daub S.a · Schreiner J.a · Kröller-Schön S.a · Wenzel P.a,b · Gori T.a · Burgin K.c · Sartor D.d · Scherhag A.d · Münzel T.a · Daiber A.a
aKardiologie, II. Medizinische Klinik, Universitätsmedizin der Johannes-Gutenberg-Universität Mainz, and bCenter of Thrombosis and Hemostasis, Mainz, Germany; cMaxia Strategies LLC and dCardiolynx AG, Basel, Switzerland

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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: May 04, 2012
Accepted: May 29, 2012
Published online: September 13, 2012
Issue release date: October 2012

Number of Print Pages: 12
Number of Figures: 7
Number of Tables: 2

ISSN: 0031-7012 (Print)
eISSN: 1423-0313 (Online)

For additional information: http://www.karger.com/PHA

Abstract

Background and Purpose: Organic nitrates represent a group of nitrovasodilators that are clinically used for the treatment of ischemic heart disease. With the present studies we synthesized and characterized new organic nitrate hybrid molecules. Compounds CLC-1265 (valsartan mononitrate) and CLC-1280 (valsartan dinitrate) are derivatives of the angiotensin receptor blocker valsartan, with CLC-1265 containing a single organic nitrate linker and CLC-1280 also containing a second, different linker. Compounds CLC-2000 (cilostazol mononitrate) and CLC-2100 (cilostazol dinitrate) are nitrate derivatives of the phosphodiesterase III inhibitor cilostazol. All compounds are designed as hybrid molecules, potentially combining the NO-donating properties of organic nitrates with the AT1-blocking activity of valsartan or the phosphodiesterase-III–inhibiting effect of cilostazol. Experimental Approach: The properties of new drugs were assessed by isometric tension recording, inhibition of platelet aggregation and formation of mitochondrial reactive oxygen and nitrogen species. Key Results: In this report, all new nitrate compounds are shown, in vitro, to induce vasodilation in the range of other, classical organic nitrates, without inducing oxidative stress or classical nitrate tolerance. In addition, the new hybrid nitrate molecules displayed superior antiaggregatory properties over classical mono- and dinitrates. Conclusions and Implications: Our results demonstrate that organic nitrates can be successfully linked to existing therapeutic molecules to create a new class of molecular entities with a potential dual mechanism of action via combining the established pharmacological properties of valsartan or cilostazol with the vasodilating properties of organic nitrates. Future experimental studies have to demonstrate whether the combined action of these compounds translates to superior therapeutic effects.

© 2012 S. Karger AG, Basel


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: May 04, 2012
Accepted: May 29, 2012
Published online: September 13, 2012
Issue release date: October 2012

Number of Print Pages: 12
Number of Figures: 7
Number of Tables: 2

ISSN: 0031-7012 (Print)
eISSN: 1423-0313 (Online)

For additional information: http://www.karger.com/PHA


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.