Potent antiplatelet effects of cyclic clofibric acid (CPIB) analogs on human platelets.
CPIB possesses antiplatelet as well as hypolipidemic activities. Two cyclic CPIB analogs, 6-phenylchroman-2-carboxylic acid (PCCA) and 6-cyclohexylchroman-2-carboxylic acid (CHCCA) were also found to be antagonists of the prostaglandin (PG)-dependent pathway of human platelet activation. PCCA and CHCCA were inhibitors of aggregation (AGG) and secretion (SEC) induced by ADP or epinephrine (E) [second waves only] and arachidonic acid (AA) with IC50 values ranging from 2.3-8.7 microM for PCCA and 3.7-12.1 microM for CHCCA. Neither compound antagonized the proaggregatory effects of the thromboxane A2 (TXA2) receptor agonist, U46619. CPIB blocked ADP and E-induced AGG and SEC (IC50's greater than 1200 microM) but not AA- or U46619-induced responses. Only CPIB blocked thrombin-induced AA release. Data showed that PCCA and CHCCA inhibited AA-induced malondialdehyde formation (IC50's = 9.3 and 11.3 microM, respectively) and thrombin-induced production of prostaglandin E2, prostaglandin F2 alpha, and TXB2 with IC50's ranging from 2.9 to 13.4 microM. PCCA and CHCCA were at least 200- to 500-fold more potent than CPIB as inhibitors of the PG-dependent pathway of human platelet activation. We conclude that PCCA and CHCCA act by inhibiting platelet cyclooxygenase activity whereas CPIB blocks the activity of phospholipase A2. Hypolipidemic PCCA and CHCCA represent a potent class of cyclooxygenase inhibitors which may be more useful than CPIB for treatment of atherosclerotic and thrombotic disorders.
Romstedt
K J
KJ
Division of Medicinal Chemistry, College of Pharmacy, Ohio State University, Columbus 43210.
Kim
S U
SU
Witiak
D T
DT
Newman
H A
HA
Feller
D R
DR
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000244:Adenosine Diphosphate / Q000494:pharmacology; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology*; D002839:Chromans / Q000494:pharmacology*; D002994:Clofibrate / Q000031:analogs & derivatives*; D002995:Clofibric Acid / Q000494:pharmacology*; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D008315:Malondialdehyde / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors
D001095:Arachidonic Acids; D001578:Benzopyrans; D002839:Chromans; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D016718:Arachidonic Acid; D008315:Malondialdehyde; D002995:Clofibric Acid; C060709:6-cyclohexylchroman-2-carboxylic acid; C060708:6-phenylchroman-2-carboxylic acid; D000244:Adenosine Diphosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013917:Thrombin; D002994:Clofibrate; D004837:Epinephrine