title: Synthesis and selective cyclooxygenase-2 inhibitory activity of a series of novel, nitric oxide donor-containing pyrazoles.
abstract: The synthesis of a series of novel pyrazoles containing a nitrate (ONO(2)) moiety as a nitric oxide (NO)-donor functionality is reported. Their COX-1 and COX-2 inhibitory activities in human whole blood are profiled. Our data demonstrate that pyrazole ring substituents play an important role in COX-2 selective inhibition, such that a cycloalkyl pyrazole (6b) was found to be a potent and selective COX-2 inhibitor. Other modifications at the 3 position of the central pyrazole ring (17b, 23b, 26b-I) enhanced COX-2 inhibitory potency. Among the pyrazoles synthesized, the oxime (23b) was identified as the most potent COX-2 selective inhibitor. Accordingly, 23b was profiled pharmacologically in the rat after oral administration and shown to possess potent antiinflammatory activity in the carrageenan-induced air-pouch model and less gastric toxicity than a standard COX-2 inhibitor when administered with background aspirin treatment. We suggest that the enhanced gastric tolerance of an NO-donor COX-2 selective inhibitor has the potential to augment the clinical profile of this drug class.
authors.affiliation: NitroMed Inc., 12 Oak Park Drive, Bedford, Massachusetts 01730, USA. rbandarage@nitromed.com
authors.forename: Ramani R
authors.initials: RR
authors.lastname: Ranatunge
authors.forename: Michael
authors.initials: M
authors.lastname: Augustyniak
authors.forename: Upul K
authors.initials: UK
authors.lastname: Bandarage
authors.forename: Richard A
authors.initials: RA
authors.lastname: Earl
authors.forename: James L
authors.initials: JL
authors.lastname: Ellis
authors.forename: David S
authors.initials: DS
authors.lastname: Garvey
authors.forename: David R
authors.initials: DR
authors.lastname: Janero
authors.forename: L Gordon
authors.initials: LG
authors.lastname: Letts
authors.forename: Allison M
authors.initials: AM
authors.lastname: Martino
authors.forename: Madhavi G
authors.initials: MG
authors.lastname: Murty
authors.forename: Stewart K
authors.initials: SK
authors.lastname: Richardson
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Schroeder
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Shumway
authors.forename: S William
authors.initials: SW
authors.lastname: Tam
authors.forename: A Mark
authors.initials: AM
authors.lastname: Trocha
authors.forename: Delano V
authors.initials: DV
authors.lastname: Young
mesh_terms: D000284:Administration, Oral; D000818:Animals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D005756:Gastritis / Q000139:chemically induced; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D008565:Membrane Proteins; D009566:Nitrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: C485226:1-(1-cyclohexyl-3-(1-(hydroxyimino)-4-(nitrooxy)butyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009566:Nitrates; D020030:Nitric Oxide Donors; D011720:Pyrazoles; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat