ABSTRACT
Indomethacin, a nonselective cyclooxygenase (COX) inhibitor, was modified in three distinct regions in an attempt both to increase cyclooxygenase-2 (COX-2) selectivity and to enhance drug safety by covalent attachment of an organic nitrate moiety as a nitric oxide donor. A human whole-blood COX assay shows the modifications on the 3-acetic acid part of the indomethacin yielding an amide-nitrate derivative 32 and a sulfonamide-nitrate derivative 61 conferred COX-2 selectivity. Along with their respective des-nitrate analogs, for example, 31 and 62, the nitrates 32 and 61 were effective antiinflammatory agents in the rat air-pouch model. After oral dosing, though, only 32 increased nitrate and nitrite levels in rat plasma, indicating that its nitrate tether served as a nitric oxide donor in vivo. In a rat gastric injury model, examples 31 and 32 both show a 98% reduction in gastric lesion score compared to that of indomethacin. In addition, the nitrated derivative 32 inducing 85% fewer gastric lesions when coadministered with aspirin as compared to the combination of aspirin and valdecoxib.
Subject(s)
Cyclooxygenase 2 Inhibitors/chemical synthesis , Indomethacin/analogs & derivatives , Indomethacin/chemical synthesis , Nitric Oxide Donors/chemical synthesis , Animals , Aspirin/adverse effects , Celecoxib , Cyclooxygenase 2 Inhibitors/adverse effects , Cyclooxygenase 2 Inhibitors/pharmacology , Drug Design , Drug Synergism , Female , Gastric Mucosa/pathology , Humans , Hydroxamic Acids/adverse effects , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Indomethacin/adverse effects , Indomethacin/pharmacology , Male , Nitric Oxide Donors/adverse effects , Nitric Oxide Donors/pharmacology , Pyrazoles/pharmacology , Rats , Rats, Sprague-Dawley , Stomach Ulcer/chemically induced , Stomach Ulcer/pathology , Structure-Activity Relationship , Sulfonamides/pharmacologyABSTRACT
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.
