NO-donor COX-2 inhibitors. New nitrooxy-substituted 1,5-diarylimidazoles endowed with COX-2 inhibitory and vasodilator properties.
A series of NO-donor diarylimidazoles derived from the lead compound Cimicoxib were synthesized and evaluated for their COX-2 inhibitory activity and their stability in whole blood as well as for vasodilator properties. The products are partly transformed into the corresponding alcohols following 24-h incubation in whole blood. All of them display good COX-1/COX-2 selectivity, but are less potent than the lead; a molecular modeling study was carried out to investigate their binding mode. The compounds are also capable of relaxing rat aorta strips precontracted with phenylephrine with a NO-dependent mechanism; this property could confer reduced cardiotoxicity with respect to traditional COX-2 inhibitors.
Chegaev
Konstantin
K
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, Italy.
Lazzarato
Loretta
L
Tosco
Paolo
P
Cena
Clara
C
Marini
Elisabetta
E
Rolando
Barbara
B
Carrupt
Pierre-Alain
PA
Fruttero
Roberta
R
Gasco
Alberto
A
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D007093:Imidazoles; D020030:Nitric Oxide Donors; D013449:Sulfonamides; D014665:Vasodilator Agents; C493522:cimicoxib