Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 1. (+/-)-(3-pyridinylbicycloheptyl)alkanoic acids.
The design, synthesis, and in vitro pharmacology of a new class of compounds exerting both thromboxane receptor antagonist and thromboxane synthase inhibitory activities is described. [(3-Pyridinyl)bicycloheptyl] alkanoic acid 9 and its analogues, designed with the help of molecular modeling, were synthesized and found to be inhibitors of thromboxane A2 (TxA2) biosynthesis in a human platelet microsomal preparation. The compounds were also found to antagonize both platelet and vascular TxA2 receptors. The compounds inhibited the U 46619 induced aggregation of human washed platelets and platelet-rich plasma and the U 46619 induced contraction of the dog saphenous vein.
Bhagwat
S S
SS
Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901.
Gude
C
C
Cohen
D S
DS
Lee
W
W
Furness
P
P
Clarke
F H
FH
D001792:Blood Platelets / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008861:Microsomes / Q000187:drug effects; D008958:Models, Molecular; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000378:metabolism*; D014961:X-Ray Diffraction
D001643:Bridged Bicyclo Compounds; D002264:Carboxylic Acids; D011725:Pyridines; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013931:Thromboxanes; D013930:Thromboxane-A Synthase