ScienceDirect - Bioorganic & Medicinal Chemistry : Design and synthesis of nitrate esters of aromatic heterocyclic compounds as pharmacological preconditioning agents

Bioorganic & Medicinal Chemistry
Volume 16, Issue 8, 15 April 2008, Pages 4523-4531

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doi:10.1016/j.bmc.2008.02.051

Design and synthesis of nitrate esters of aromatic heterocyclic compounds as pharmacological preconditioning agents

Theano Fotopoulou^a^,^b, Efstathios K. Iliodromitis^c, Maria Koufaki^a^,^,, Andrew Tsotinis^b, Anastasia Zoga^c, Vassilis Gizas^c, Anastasia Pyriochou^d, Andreas Papapetropoulos^d, Ioanna Andreadou^b^,^, and Dimitrios Th Kremastinos^c

^aNational Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, 48, Vas. Constantinou Avenue, 11635 Athens, Greece ^bFaculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou, 157 71 Athens, Greece ^cSecond University Department of Cardiology, Medical School, Attikon General Hospital, University of Athens, 12462 Athens, Greece ^dLaboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Greece

Received 19 November 2007;

revised 8 February 2008;

accepted 15 February 2008.

Available online 20 February 2008.

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Abstract

Ischemic preconditioning (IPC) constitutes an endogenous protective mechanism in which one or more brief periods of myocardial ischemia and reperfusion render the myocardium resistant to a subsequent more-sustained ischemic insult. Pharmacological preconditioning represents an ideal alternative of IPC. We now describe the design and synthesis of indole, quinoline, and purine systems with an attached pharmacophoric nitrate ester group. The indole and quinoline derivatives 4 and 5 possess structural features of the nitrate containing K_ATP channel openers. Purine analogues 11 and 12, substituted at the position 6 by a piperidine moiety and at position 9 by an alkyl nitrate, could combine the effects of the nitrate containing K_ATP channel openers and those of adenosine. Compound 13 bears the nicotinamide moiety of nicorandil instead of nitrate ester. Compounds 4, 5, and 11 reduced infarction and the levels of malondialdehyde (MDA) at reperfusion in anesthetized rabbits. Compounds 12 and 13 did not significantly reduce the infarct size. Analogues 4 and 5 increased cGMP and MDA during ischemia, while combined analogue 4 and mitoK_ATP blocker 5-hydroxydecanoic acid (5-HD) abrogated this benefit suggesting an action through mitoK_ATP channel opening. Treatment with derivative 11 combined with 5-HD as well as treatment with 11 and adenosine receptor blocker 8-(p-sulfophenyl)theophylline (SPT) did not abrogate cardioprotection. Compound 11 is a lead molecule for the synthesis of novel analogues possessing a dual mode of action through cGMP–mitoK_ATP channel opening-free radicals and through adenosine receptors.