title: Synthesis and evaluation of multi-functional NO-donor/insulin-secretagogue derivatives for the treatment of type II diabetes and its cardiovascular complications.
abstract: Although there is a significant effort in the discovery of effective therapies to contrast both the pathological endocrine and metabolic aspects of diabetes and the endothelial dysfunction associated with this disease, no hypoglycemic drug has been proven to defeat the cardiovascular complications associated with type II diabetes. The aim of this research was to design new compounds exhibiting a double profile of hypoglycemic agents/NO-donors. The synthesis of molecules obtained by the conjunction of NO-donor moieties with two oral insulin-secretagogue drugs (repaglinide and nateglinide) was reported. NO-mediated vasorelaxing effects of the synthesized compounds were evaluated by functional tests on isolated endothelium-denuded rat aortic rings. The most potent molecule (4) was tested to evaluate the hypoglycemic and the anti-ischemic cardioprotective activities. This study indicates that 4 should represent a new insulin-secretagogue/NO-donor prodrug with an enhanced cardiovascular activity, which may contrast the pathological aspects of diabetes and endowed of cardioprotective activity.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Digiacomo
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
authors.forename: Alma
authors.initials: A
authors.lastname: Martelli
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Testai
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
authors.forename: Annalina
authors.initials: A
authors.lastname: Lapucci
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Breschi
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno, 6, 56126 Pisa, Italy. Electronic address: calderone@farm.unipi.it.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calderone
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno, 6, 56126 Pisa, Italy. Electronic address: simona.rapposelli@farm.unipi.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002316:Cardiotonic Agents; D007004:Hypoglycemic Agents; D007328:Insulin; D020030:Nitric Oxide Donors
keywords: Cardioprotection; Hybrid drugs; Hypoglycemic; Insulin-secretagogue drug; NO-donor; NO-releasing drugs