Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 5. Synthesis and evaluation of enantiomers of 8-[[(4-chlorophenyl)sulfonyl]amino]-4-(3-pyridinylalkyl)octanoic acid.
The enantiomers of 8-[[(4-chlorophenyl)sulfonyl]amino]-4-(3-pyridinylpropyl)octanoic acid (1) and its pyridinyl ether analog (2) were synthesized using the highly diastereoselective method of alkylation of acyloxazolidinone. These enantiomerically pure compounds were compared with the corresponding racemic compounds 1 and 2 for their in vitro activity. Compounds 1, 1R, and 1S and 2,2S, and 2R were equipotent as thromboxane receptor antagonists (TxRAs) and thromboxane synthase inhibitors (TxSIs) (IC50 = 2-30 nM). Upon oral administration to guinea pigs, the enantiomers inhibited the ex vivo U 46619-induced platelet aggregation with potency similar to that of the corresponding racemic compound. This indicates that the enantiomers have pharmacologic profile and bioavailability similar to that of the corresponding racemic compound.
Bhagwat
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Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901.
Gude
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Cohen
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Dotson
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Mathis
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Lee
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Furness
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D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D002210:Caprylates / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors
D002210:Caprylates; D011450:Prostaglandin Endoperoxides, Synthetic; D011725:Pyridines; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; C078274:CGS 22652; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013930:Thromboxane-A Synthase