1. Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 3. Pyridinylalkyl-substituted 8-[(arylsulfonyl)amino]octanoic acids
- Author
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Main Alan J, David Cohen, Patricia Furness, Marissa Louzan, Shripad S. Bhagwat, Clay Boswell, Robert Goldstein, Warren Lee, and Candido Gude
- Subjects
Platelet Aggregation ,Pyridines ,Stereochemistry ,Receptors, Thromboxane ,Thromboxane receptor ,Structure-Activity Relationship ,Thromboxane A2 ,chemistry.chemical_compound ,Dogs ,Biosynthesis ,Drug Discovery ,Animals ,Humans ,Vasoconstrictor Agents ,Structure–activity relationship ,biology ,Muscle, Smooth ,Biological activity ,Prostaglandin Endoperoxides, Synthetic ,Biochemistry ,chemistry ,Enzyme inhibitor ,15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ,biology.protein ,Molecular Medicine ,Platelet aggregation inhibitor ,Thromboxane-A Synthase ,Thromboxane-A synthase ,Caprylates ,Platelet Aggregation Inhibitors - Abstract
A series of 8-[(arylsulfonyl)amino]octanoic acids substituted with a pyridinylalkyl group along the chain were synthesized and tested in vitro for their ability to both antagonize the binding of thromboxane A2 to its receptors and to inhibit the thromboxane synthase enzyme. This series of compounds were found to inhibit the U 46619-induced aggregation of human platelets and the U 46619-induced contraction of dog saphenous vein. The compounds also inhibited TxA2 biosynthesis in a human microsomal platelet preparation. The relative position of the pyridinylalkyl and arylsulfonamide groups had significant effects on the thromboxane receptor antagonist (TxRA) activity and thromboxane synthase inhibitor (TxSI) activity. Compounds with the pyridine ring at the 7- or 8-position of the octanoic acid side chain were weakly active as TxSI but behaved as potent TxRA at the platelet receptor for TxA2. However, these compounds were agonists at the vascular receptor. Substitution of the pyridinylalkyl group at the 2- or 3-position resulted in compounds with potent TxSI activity and weak TxRA activity. The activity profile of the compounds with the pyridinylalkyl substitution at the 4-, 5-, or 6-position was very desirable. Compound 22 with a pyridinylpropyl substituent at the 4-position was found to display extremely potent TxRA and TxSI properties.
- Published
- 1992