title: NO-donor COX-2 inhibitors. New nitrooxy-substituted 1,5-diarylimidazoles endowed with COX-2 inhibitory and vasodilator properties.
abstract: 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.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, Italy.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Chegaev
authors.forename: Loretta
authors.initials: L
authors.lastname: Lazzarato
authors.forename: Paolo
authors.initials: P
authors.lastname: Tosco
authors.forename: Clara
authors.initials: C
authors.lastname: Cena
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marini
authors.forename: Barbara
authors.initials: B
authors.lastname: Rolando
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.forename: Alberto
authors.initials: A
authors.lastname: Gasco
mesh_terms: 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
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D007093:Imidazoles; D020030:Nitric Oxide Donors; D013449:Sulfonamides; D014665:Vasodilator Agents; C493522:cimicoxib