Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 2. Synthesis and biological activity of 8-(benzenesulfonamido)-7-(3-pyridinyl)octaonic acid and related compounds.
A series of arylsulfonamide alkanoic acids substituted with a 3-pyridinyl group along the aliphatic chain were synthesized and tested in vitro for their ability to antagonize thromboxane A2 (TxA2) receptors and inhibit thromboxane synthase. These compounds were found to potently inhibit the U 46619-induced aggregation of human platelets and to also inhibit TxA2 biosynthesis in a human microsomal platelet preparation. However, some members of the series, notably compound 21, were found to display agonist activity on the rabbit aorta TxA2 receptor. This unwanted agonist activity appeared to be related to the presence of a substituent beta to the arylsulfonamido group.
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Research Department, Pharmaceuticals Division, CIBA-GEIGY Corporation, Summit, New Jersey 07901.
Goldstein
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R
Cohen
D S
DS
Furness
P
P
Lee
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W
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D002210:Caprylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D017482:Receptors, Thromboxane / Q000187:drug effects*; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D002210:Caprylates; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D011725:Pyridines; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; C078270:8-(benzenesulfonamido)-7-(3-pyridinyl)octanoic acid; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013930:Thromboxane-A Synthase