2-[3-[2-(4,5-Diphenyl-2-oxazolyl) ethyl] phenoxy] acetic acid (BMY 42393): a new, structurally-novel prostacyclin partial agonist: 1). Inhibition of platelet aggregation and mechanism of action.
BMY 42393, (2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid), is a new prostacyclin partial agonist that inhibited ADP, collagen and thrombin-induced platelet aggregation (IC50 range 0.3 - 2.0 microM). BMY 42393 stimulated platelet adenylate cyclase activity (EC50 = 25 nM), however, the maximal activation was 75-80% of that observed with maximal iloprost or PGE1. Platelets treated with BMY 42393 showed an elevation of cAMP levels and activation of cAMP-dependent protein kinase. BMY 42393 also inhibited thrombin-induced elevation of intracellular free calcium. BMY 42393 competed for radiolabeled iloprost and PGE1 binding to platelet membranes (IC50; 170 nM and 130 nM, respectively); however, it had little effect on radiolabeled PGE2, PGD2, or SQ 29548 binding. These studies indicate that BMY 42393 is a novel platelet aggregation inhibitor which acts by stimulation of platelet prostacyclin receptors to elevate platelet cAMP levels.
Department of Cardiovascular Biochemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492.
S M
SM
Seiler
C L
CL
Brassard
M E
ME
Federici
J O
JO
Buchanan
G B
GB
Zavoico
J S
JS
Fleming
N A
NA
Meanwell
D000262:Adenylyl Cyclases / Q000097:blood; D001792:Blood Platelets / Q000201:enzymology; D002118:Calcium / Q000097:blood; D000242:Cyclic AMP / Q000097:blood; D017868:Cyclic AMP-Dependent Protein Kinases / Q000097:blood; D011464:Epoprostenol; D006801:Humans; D015394:Molecular Structure; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D010642:Phenoxyacetates / Q000737:chemistry / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D013329:Structure-Activity Relationship
D010080:Oxazoles; D010642:Phenoxyacetates; D010975:Platelet Aggregation Inhibitors; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; C080116:BMY 42393; D011464:Epoprostenol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D002118:Calcium