title: R 68 070: thromboxane A2 synthetase inhibition and thromboxane A2/prostaglandin endoperoxide receptor blockade combined in one molecule--I. Biochemical profile in vitro.
abstract: R 68 070 or (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]- methylen]amino]oxy] pentanoic acid (Janssen Research Foundation, Belgium) combines specific thromboxane A2 (TXA2) synthetase inhibition with TXA2/prostaglandin endoperoxide receptor blockade in one molecule. In vitro, the compound specifically inhibits the production of TXB2 from [14C] arachidonic acid by washed human platelets (IC50 = 8.2 X 10(-9) M) and by platelet microsomes (IC50 = 3.6 X 10(-9) M), of MDA (IC50 = 1.91 X 10(-8) M) and of TXB2 (IC50 = 1.47 X 10(-8) M) by thrombin-coagulated human platelet-rich plasma (P.R.P.) and whole blood respectively and increases the levels of PGD2, PGE2, PGF2 alpha and 6-keto-PGF1 alpha. The activity of cyclo-oxygenase-, prostacyclin synthetase-, 5-, 12- and 15-lipoxygenase-enzymes are not affected. Additionally, R 68 070 inhibits human platelet aggregation in P.R.P. induced by U 46619 3 X 10(-7) M to 2 X 10(-6) M (IC50 = 2.08 X 10(-6) M to 2.66 X 10(-5) M, collagen 0.5 to 2 micrograms/ml (IC50 = 2.85 X 10(-6) M to 4.81 X 10(-5) M), arachidonic acid 7.5 X 10(-4) M to 2 X 10(-3) M (IC50 = 2.1 X 10(-8) M to 3.3 X 10(-8) M) and the U 46619 (1 X 10(-7) M)-induced accumulation of [32P] phosphatidic acid (IC50 = 5.24 X 10(-7) M) in washed human platelets.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Haematology, Janssen Research Foundation, Beerse, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: De Clerck
authors.forename: J
authors.initials: J
authors.lastname: Beetens
authors.forename: D
authors.initials: D
authors.lastname: de Chaffoy de Courcelles
authors.forename: E
authors.initials: E
authors.lastname: Freyne
authors.forename: P A
authors.initials: PA
authors.lastname: Janssen
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000097:blood; D006801:Humans; D066298:In Vitro Techniques; D010421:Pentanoic Acids / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000097:blood; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011453:Prostaglandins / Q000032:analysis; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D012756:Sheep; D013929:Thromboxane B2 / Q000032:analysis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014631:Valerates / Q000494:pharmacology*
chemical_list: D001095:Arachidonic Acids; D010421:Pentanoic Acids; D010716:Phosphatidylinositols; D010975:Platelet Aggregation Inhibitors; D011453:Prostaglandins; D011725:Pyridines; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D014631:Valerates; D013929:Thromboxane B2; D000242:Cyclic AMP; D013930:Thromboxane-A Synthase; C060219:ridogrel