Synthesis and selective cyclooxygenase-2 inhibitory activity of a series of novel, nitric oxide donor-containing pyrazoles.
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.
Ranatunge
Ramani R
RR
NitroMed Inc., 12 Oak Park Drive, Bedford, Massachusetts 01730, USA. rbandarage@nitromed.com
Augustyniak
Michael
M
Bandarage
Upul K
UK
Earl
Richard A
RA
Ellis
James L
JL
Garvey
David S
DS
Janero
David R
DR
Letts
L Gordon
LG
Martino
Allison M
AM
Murty
Madhavi G
MG
Richardson
Stewart K
SK
Schroeder
Joseph D
JD
Shumway
Matthew J
MJ
Tam
S William
SW
Trocha
A Mark
AM
Young
Delano V
DV
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
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