Thrombin receptor antagonists. Structure-activity relationships for the platelet thrombin receptor and effects on prostacyclin synthesis by human umbilical vein endothelial cells.
Structure-activity studies on a series of analogues of N-(3-methyl-S-(1-pyrrolidinyl carbonyl) butyl)-D-alanine ethyl ester hydrochloride (SC42619) have defined the features of this dipeptide analogue required for observation of thrombin receptor antagonist activity on the human platelet. The affinity for SC42619, and for its structural analogue SC43583 is enhanced by pretreatment of the platelets with chymotrypsin. Endothelial cell prostacyclin (PGI2) synthesis induced by thrombin and trypsin is selectively inhibited by SC42619 provided that prolonged exposure to this antagonist is avoided. However inhibition of PGI2 synthesis by SC42619 is not overcome by increasing the thrombin concentration. The data provide further support for identification of SC42619 and certain of its analogues as selective antagonists at the platelet thrombin receptor but suggest that these compounds may have more complex, and possibly non-selective effects on the endothelial cell.
Ruda
E M
EM
Department of Biochemistry, King's College, Strand, London, U.K.
Scrutton
M C
MC
Manley
P W
PW
Tuffin
D P
DP
D000991:Antithrombins / Q000138:chemical synthesis / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D002918:Chymotrypsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis*; D006801:Humans; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000187:drug effects*; D018179:Receptors, Thrombin; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000494:pharmacology
D000991:Antithrombins; D010455:Peptides; D011956:Receptors, Cell Surface; D018179:Receptors, Thrombin; C051258:SC 42619; D011464:Epoprostenol; D002918:Chymotrypsin; D013917:Thrombin