NO-glibenclamide derivatives: Prototypes of a new class of nitric oxide-releasing anti-diabetic drugs Vincenzo Calderone a, * , Simona Rapposelli b , Alma Martelli a , Maria Digiacomo b , Lara Testai a , Scilla Torri c , Piero Marchetti c , Maria C. Breschi a , Aldo Balsamo b a Dipartimento di Psichiatria, Neurobiologia, Farmacologia, Biotecnologie, Università di Pisa, Via Bonanno, 6, I-56126 Pisa, Italy b Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno, 6, I-56126 Pisa, Italy c Dipartimento di Endocrinologia e Metabolismo, Ortopedia e Traumatologia, Medicina del Lavoro, Università di Pisa, Via Paradisa, 2, I-56124 Pisa, Italy article info Article history: Received 20 March 2009 Revised 18 June 2009 Accepted 20 June 2009 Available online 27 June 2009 Keywords: Hybrid drugs Diabetes Nitric oxide Nitrates Sulfanylurea Glybenclamide abstract Endothelial dysfunction and consequent reduction of biosynthesis of endogenous nitric oxide (NO) play an important pathogenetic role in the cardiovascular complications associated with type II diabetes. In this work, the hybrid drugs 3a and 3b, nitrooxymethylbenzoate-derivatives of 1 (which is a hydroxylated active metabolite of glibenclamide 2), are reported. The pharmacodynamic characterization of 3b showed that its hypoglycaemic activity is enriched with additional NO-donor effects, conferring vasorelaxing and anti-platelet properties of potentially great usefulness for diabetes-related cardiovascular disorders. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction Type II diabetes mellitus is presently viewed as a multifactorial disease in which both metabolic and cardiovascular disorders co- exist and are somehow correlated, although the exact mechanisms of this possible interaction are not yet completely understood. 1 Really, the metabolic aspects of this complex disease are almost al- ways associated with microvascular complications, leading to retinopathy, neuropathy and nephropathy. Also important macro- vascular problems (myocardial ischemia, cerebrovascular acci- dents, hypertension, peripheral vasculopathy) accompain (and sometimes anticipate) type II diabetes 2–4 and really represent the main causes of mortality in diabetic patients. 5 To further remark the close correlation between cardiovascular and metabolic as- pects in type II diabetes, it is widely observed that agents improv- ing insulin sensitivity show also pressure lowering effects 6,7 and, conversely, antihypertensive drugs can lead to an improvement of insulin sensitivity in type II diabetic patients. 8 The pathogenesis of diabetic cardiovascular complications seems to involve structural aspects, such as glycation of wall com- ponents of blood vessels, and functional aspects. The functional impairment, in particular, is substantially due to endothelial dys- function, that is, the incapacity of vascular endothelium to play correctly its fundamental role of regulation of circulatory homeo- stasis, through biosynthesis and release of nitric oxide (NO) and other endothelial factors. 9 Such a reduced bioavailability of NO, with its pivotal properties (for example, the vasorelaxing and anti-platelet ones), synergizes with the metabolic alterations (dyslipidaemia, glycation end-products, oxidative stress), resulting in a dramatically increased incidence of atherosclerosis, blood hypercoagulability, vascular inflammation and remodeling, exacer- bated vasospastic responses, hypertension, coronaropathy and stroke. 8,10 Therefore, type II diabetes patients are frequently forced to fol- low multi-pharmacological therapeutic regimens composed by several drugs, targeted to glycaemic control on one hand, and to reduction of cardiovascular complications on the other hand. In particular, the usual anti-diabetics (biguanides, sulfonylureas, thia- zolidinediones, etc.) are largely associated with drugs targeting hypertension (ACE-inhibitors, sartans, calcium channel blockers, etc.), dyslipidaemia (statins, fibrates, etc.) and/or platelet activa- tion/aggregation (aspirin, clopidogrel, etc.). 8,11 In the last years, the development of new pharmacodynamic hybrids or ‘chimeras’, that is, molecules showing two (or more) mechanisms of action, represented an encouraging field of research and furnished some interesting examples of drugs of potentially great usefulness, especially for complex cardiovascular diseases of multifactorial nature. 12 The addition of cleavable NO-releasing molecular portions to well-known ‘old’ drugs has been frequently 0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2009.06.049 * Corresponding author. Tel.: +39 (0)50 2219589; fax: +39 (0)50 2219609. E-mail address: calderone@farm.unipi.it (V. Calderone). Bioorganic & Medicinal Chemistry 17 (2009) 5426–5432 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc