Synthesis and Selective Cyclooxygenase-2 Inhibitory Activity of a Series of Novel, Nitric Oxide Donor-Containing Pyrazoles
| Autor: | David R. Janero, Ramani R. Ranatunge, Matthew J. Shumway, Delano V. Young, James L. Ellis, Joseph D. Schroeder, S. William Tam, David S. Garvey, A. Mark Trocha, L. Gordon Letts, Madhavi G. Murty, Michael E. Augustyniak, Richard A. Earl, Upul K. Bandarage, Allison M. Martino, Stewart K. Richardson |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Stereochemistry Administration Oral In Vitro Techniques Pyrazole Chemical synthesis Sulfone Nitric oxide Rats Sprague-Dawley Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Animals Humans Moiety Structure–activity relationship Cyclooxygenase Inhibitors Nitric Oxide Donors Nitrates Cyclooxygenase 2 Inhibitors biology Membrane Proteins Rats Isoenzymes chemistry Cyclooxygenase 2 Prostaglandin-Endoperoxide Synthases Enzyme inhibitor Gastritis Cyclooxygenase 1 biology.protein Pyrazoles Molecular Medicine Female Cyclooxygenase |
| Zdroj: | Journal of Medicinal Chemistry. 47:2180-2193 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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