Differential eudismic ratios in the antagonism of human platelet function by phenoxy- and thiophenoxyacetic acids.
The antilipidemic drug clofibric acid (CPIB) exhibits antiplatelet effects. In order to examine the role of enantioselectivity and hydrophobicity, the mono(desmethyl) enantiomers of 2-(4-chlorophenoxy)propanoic acid (CPPA), related butanoate homologs, 2-(4-chlorophenoxy)butanoic acid (CPBA), thioether relatives, 2-(4-chlorothiophenoxy)propanoic acid (CTPA) and corresponding butanoate homologs, 2-(4-chlorothiophenoxy)butanoic acid (CTBA) were studied. All compounds inhibit prostaglandin-dependent human platelet aggregation and serotonin secretion induced by ADP. For the phenoxy acid series, (+)-(R)-CPPA is 5-fold more potent than either (-)-(S)-CPPA or CPIB giving a rank order potency of (+)-(R)-CPPA > (+)-(R)-CPBA > (-)-(S)-CPPA > (-)-(S)-CPBA. With the exception of (-)-(S)-CTPA, all thiophenoxy acid enantiomers are less potent than their respective phenoxy acid isomers [(+)-(R)-CTPA > (-)-(S)-CTPA > (+)-(R)-CTBA > (-)-(S)-CTBA]. The same rank order of potencies are observed against responses induced by arachidonic acid (AA) with the exception of CPIB which is inactive. However, inhibition of thrombin-induced [3H]-AA release by phenoxyacetic acids is not stereoselective but correlates with hydrophobicity.
Romstedt
K J
KJ
Division of Pharmacology and Medicinal Chemistry, Columbus, Ohio 43210-1291, USA.
Lei
L P
LP
Feller
D R
DR
Witiak
D T
DT
Loiodice
F
F
Tortorella
V
V
D016718:Arachidonic Acid / Q000378:metabolism; D002995:Clofibric Acid / Q000031:analogs & derivatives*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D010642:Phenoxyacetates / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000960:Hypolipidemic Agents; D010642:Phenoxyacetates; D010975:Platelet Aggregation Inhibitors; D016718:Arachidonic Acid; D002995:Clofibric Acid