NO-Releasing Hybrids of Cardiovascular Drugs

Abstract

Nitric oxide (NO) is an endogenous compound, which plays a fundamental role in the modulation of the function of the cardiovascular system, where it induces vasorelaxing and antiplatelet responses, mainly through the stimulation of guanylate cyclase and the increase of cGMP. Many drugs of common, time-honoured clinical use (for example, glycerol trinitrate and all the vasodilator nitrites and nitrates) act via the release of exogenous NO, thus mimicking the effects of the endogenous factor. In the last few years, a revision of the "one-compound-one-target" paradigm has led pharmacologists and pharmaceutical chemists to develop new classes of molecules which combine different pharmacodynamic properties. This innovative pharmacological/pharmaceutical strategy has produced hybrid drugs, with a dual mechanism of action: a) the slow release of nitric oxide and b) another fundamental pharmacodynamic profile. These drugs have been obtained by inserting appropriate NO-donor chemical groups (i.e. nitrate esters, nitrosothiols, etc.), linked to a known drug, by means of a variable spacer moiety. These new pharmacodynamic hybrids present the advantage of combining a basic mechanism of action (for example, cyclooxygenase inhibition, beta-antagonism or ACE inhibition) with a slow release of NO, which may be useful either to reduce adverse side effects (for example, the gastrotoxicity of NSAIDs), or to improve the effectiveness of the drug (for example, conferring direct vasorelaxing and antiplatelet effects on an ACE-inhibitor). The aim of this review is to present the chemical features of NO-releasing hybrids of cardiovascular drugs, and to explain the pharmacological improvements obtained by the addition of the NO-donor properties.

Hydrogen sulphide: novel opportunity for drug discovery

“…This research has produced an impressive number of interesting molecules which act simultaneously on two or more relevant targets (receptors and/or enzymes) deeply involved in the control of the cardiocirculatory function, such as the angiotensin converting enzyme, AT1 receptors for angiotensin II, Mas receptor for angiotensin (1)(2)(3)(4)(5)(6)(7), neutral endopeptidase, endothelin converting enzyme, endothelin receptors, etc. 187,188 Of course, given the pivotal role of NO in almost all aspects related to the regulation of blood circulation, it is quite obvious that one of the most fruitful strategies in the field of pharmacodynamic hybrids has been focused on the development of NO-releasing hybrid drugs, often obtained through the conjugation of suitable NO-releasing moieties to ''old'' conventional drugs (CV and nonCV) already known to possess other mechanisms of action, 16,17 in order to reduce possible adverse effects and/or improve their therapeutic impact.…”

“…Several studies have clarified its multiple physiological roles and mechanisms of action, and many molecules able to release NO have been proposed as new pharmacotherapeutic tools. 16,17 By contrast, CO seems to have little chance of pharmacological development, because of its high toxicity and scarce manageability. Concerning H 2 S, early studies indicate that this gasotransmitter might represent a truly attractive candidate in the field of endogenous gaseous modulators; in fact, it possesses almost all the beneficial CV effects exhibited by NO.…”

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

“…A promising strategy to overcome the disadvantages of organic nitrates is the covalent link between the nitrate function and another vasoactive compound potentially combining the advantages of both drugs, so-called hybrid molecules [9]. There are several reports in the literature on nitrate hybrid molecules: nicorandil, a potassium channel opener with nitrate function [10,11]; 2NTX-99, a thromboxane synthase inhibitor and thromboxane receptor antagonist and NO-releasing group [12]; GT-094, a nonsteroidal anti-inflammatory drug with NO function [13]; the antifungal drug ketoconazole with a diazen-1-ium-1,2-diolate or an organic nitrate moiety [14]; NO-donor-tacrine hybrids as hepatoprotective anti-Alzheimer drug candidates [15]; the NicOx compound nitroaspirin, reviewed in Gresele and Momi [16]; NO-releasing celecoxib analogs, inhibitors of inducible cyclooxygenase [17]; a vitamin E analog with NO donor function [18].…”

Novel renin inhibitors containing derivatives of N‐alkylleucyl‐β‐hydroxy‐γ‐amino acids

“…We expect dual mechanism of action of these drugs-besides of the inhibitory activity described earlier, the L-arginine is expected to be a source of endogenous nitrogen monoxide (NO)-a strong vasodilatory agent [45]. Such a novel class of hybrid drugs, which in addition to their principal hypotensive activity, release also nitrogen monoxide, has been developed recently [46][47][48][49]. We assume that because of the presence of guanidine residues, besides their renin inhibitory activity, the compounds 7 and 11, after removing the protective NO 2 group, may also be NO donors [50].…”