title: Pharmacological profile of BMS 180,291: a potent, long-acting, orally active thromboxane A2/prostaglandin endoperoxide receptor antagonist.
abstract: 180,291 1S-(1 alpha, 2 alpha, 3 alpha, 4 alpha)-2-[[3-[4- [(pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept- 2- yl]methyl]benzenepropanoic acid (BMS) is a potent and highly selective antagonist of thromboxane A2/prostaglandin endoperoxide (TP) receptors. In human platelet-rich plasma, BMS 180,291 inhibited platelet aggregation induced by arachidonate (800 microM) and U-46,619 (10 microM) with respective IC50 values of 7 +/- 1 (S.E.M.) and 21 +/- 2 nM. Inhibition of both the rate and full extent of 11,9-epoxymethano-prostaglandin H2 (U-46,619)-induced platelet aggregation were insurmountable at antagonist concentrations > 10 nM, but BMS 180,291 antagonized U-46,619-induced platelet shape change competitively with a KB of 11 +/- 2 nM. BMS 180,291 concentrations < or = 1 mM did not inhibit platelet aggregation induced by high concentrations of ADP (20 microM) or human alpha-thrombin (1 U/ml). BMS 180,291 inhibited binding of [3H]1S-[1 alpha,2 alpha(5Z),3 alpha,4 alpha]-7-[3-[[2- [(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]-hept-2- yl]-5-heptenoic acid to human platelet membranes with a kd of 4.0 +/- 1.0 nM and slope factor of 1.06 +/- 0.13. U-46,619-induced concentrations of rat aortae were competitively antagonized by BMS 180,291 with a KB of 0.6 +/- 0.1 nM. Aortic responses to norepinephrine, serotonin and angiotensin II were not inhibited by BMS 180,291 at 1 microM. U-46,619-induced contractions of guinea pig tracheal rings were antagonized in an almost all-or-none manner, with maximal blockade at > or = 1 nM BMS 180,291, but little effect at lower concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Cardiovascular Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey.
authors.forename: M L
authors.initials: ML
authors.lastname: Ogletree
authors.forename: D N
authors.initials: DN
authors.lastname: Harris
authors.forename: W A
authors.initials: WA
authors.lastname: Schumacher
authors.forename: M L
authors.initials: ML
authors.lastname: Webb
authors.forename: R N
authors.initials: RN
authors.lastname: Misra
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002417:Cattle; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D015232:Dinoprostone / Q000096:biosynthesis; D005231:Fatty Acids, Unsaturated; D006168:Guinea Pigs; D006801:Humans; D006834:Hydrazines / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D010080:Oxazoles / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013552:Swine; D013929:Thromboxane B2 / Q000096:biosynthesis; D014132:Trachea / Q000187:drug effects / Q000502:physiology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010080:Oxazoles; D011422:Propionates; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C055662:prostaglandin endoperoxide receptor; D013929:Thromboxane B2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; C078904:ifetroban; D015232:Dinoprostone