Therapeutic Potential of Nitrate Esters of Commonly Used Drugs

Abstract

Organic nitrates, such as nitroglycerin, have been used in clinical practice for more than one century for the treatment of angina, even before the identification of Nitric Oxide (NO) as the so-called Endothelium Derived Relaxing Factor (EDRF). Recently, multiple functions of this molecule in biology and pathophysiology have been discovered and alterations in the NO signalling pathway have often been associated with disease progression in mammals, providing a strong rationale for the use of NO as a potential drug. To have a therapeutic benefit from NO properties, an elegant approach has been designed coupling well-known existing drugs with moieties able to slowly release NO following enzymatic metabolism. "Hybrid nitrates", in which activities of both the native drug and NO are present, have been obtained with the aim of originating safer and more active drugs. The technology consists in the choice of the appropriate chemical spacer arm carrying the nitric ester in order to obtain the best pharmacodynamic and pharmacokinetic profile. The connecting linkers already explored are of different chemical structure, ranging from aliphatic chains to heteroaromatic rings. The molecules so far obtained have already demonstrated their potential therapeutic interest in both pharmacological tests and clinical trials. In this review, we describe the approach and the possibility of generating new chemical entities, combining well-known drugs with an NO-donating moiety in order to increase activity and safety, along with examples of their activity and potential therapeutic application in different pathologies. A few significant examples of molecules in the early preclinical stage, as well as in advanced clinical development will be described.

Selective modulation of amyloid‐β peptide degradation by flurbiprofen, fenofibrate, and related compounds regulates Aβ levels

“…All cell culture supplies, murine biotinylated 4G8 and 6E10 antibodies, human Ab enzymelinked immunosorbent assay (ELISA) kit, and streptavidin Dynabeads T1 were purchased from Invitrogen (Carlsbad, CA, USA). HCT-1026 was synthesized according to the literature (Bolla et al 2005) and fenofibric acid was synthesized by simple saponification of fenofibrate.…”

Risk Factors for Gastrointestinal Complications in Aspirin Users: Review of Clinical and Experimental Data

“…Already in common use, nitroglycerin is an example of a relatively inexpensive nitrate, compared with the new class of nitric oxide (NO) donor agents in development [79][80][81]. The use of nitroglycerin/nitrate specifically as prophylaxis against gastric ulcerations induced by long-term aspirin treatment, however, is not standard of practice.…”

Pharmacological Characterization of 2NTX-99 [4-Methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide], a Potential Antiatherothrombotic Agent with Antithromboxane and Nitric Oxide Donor Activity in Platelet and Vascular Preparations

“…The in vivo experiments indicate that 2NTX-99 represents a novel chemical entity, not a prodrug or a mutual prodrug of two active molecules (Bolla et al, 2005), that is absorbed and exerts its sustained action in intact form. As a consequence, the multiplicity of its diverse effects, observed in vitro in a balanced fashion, can be elicited in vivo consistently with a sole pharmacokinetic pathway of absorption and distribution.…”