NO-glibenclamide derivatives: prototypes of a new class of nitric oxide-releasing anti-diabetic drugs.
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.
Calderone
Vincenzo
V
Dipartimento di Psichiatria, Neurobiologia, Farmacologia, Biotecnologie, Università di Pisa, Via Bonanno, 6, I-56126 Pisa, Italy. calderone@farm.unipi.it
Rapposelli
Simona
S
Martelli
Alma
A
Digiacomo
Maria
M
Testai
Lara
L
Torri
Scilla
S
Marchetti
Piero
P
Breschi
Maria C
MC
Balsamo
Aldo
A
D000818:Animals; D001011:Aorta / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000188:drug therapy*; D005905:Glyburide / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
D007004:Hypoglycemic Agents; D007328:Insulin; D020030:Nitric Oxide Donors; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D005905:Glyburide