Structure-activity relationships associated with 3,4,5-triphenyl-1H-pyrazole-1-nonanoic acid, a nonprostanoid prostacyclin mimetic
| Autor: | Nicholas A. Meanwell, Michael J. Rosenfeld, J. Stuart Fleming, Marianne E. Federici, J.O. Buchanan, J. J. Kim Wright, C.L. Brassard, Steven M. Seiler |
|---|---|
| Rok vydání: | 1992 |
| Předmět: |
Blood Platelets
Stereochemistry Carboxylic acid Receptors Prostaglandin Nonanoic acid Prostacyclin In Vitro Techniques Pyrazole Receptors Epoprostenol Cyclase Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Animals Humans Platelet Iloprost Receptor IC50 chemistry.chemical_classification Imidazoles Epoprostenol Rats chemistry Biochemistry Pyrazoles Molecular Medicine Rabbits Platelet Aggregation Inhibitors Adenylyl Cyclases medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 35:389-397 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00080a028 |
| Popis: | A series of phenylated pyrazoloalkanoic acid derivatives were synthesized and evaluated as inhibitors of ADP-induced human platelet aggregation. 3,4,5-Triphenyl-1H-pyrazole-1-nonanoic acid (8d), with an IC50 of 0.4 microM, was the most potent inhibitor identified in this study. Biochemical studies determined that 8d increased intraplatelet cAMP accumulation and stimulated platelet membrane-bound adenylate cyclase in a concentration-dependent fashion. Displacement of [3H]iloprost by 8d from platelet membranes indicated that the platelet prostacyclin (PGI2) receptor is the locus of biological action. Structure-activity studies demonstrated that the minimum structural requirements for binding to the platelet PGI2 receptor and inhibition of ADP-induced platelet aggregation within this series are a vicinally diphenylated pyrazole substituted with an omega-alkanoic acid side chain eight or nine atoms long. Potency depended upon both side-chain length and its topological relationship with the two phenyl rings. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|