Interphenylene 7-oxabicyclo[2.2.1]heptane thromboxane A2 antagonists. Semicarbazone omega-chains.
A series of chiral interphenylene 7-oxabicyclo[2.2.1]heptane semicarbazones 19-26 were prepared and evaluated for their in vitro thromboxane (TxA2) antagonistic activity and in vivo duration of action. The potency of 19-26 was found to highly dependent on the substitution pattern of the interphenylene ring and decreased in the order ortho greater than meta much greater than para. SQ 35,091 (25), [1S-(1 alpha,2 alpha,3 alpha,4 alpha)]-2-[[3-[[[(phenylamino) carbonyl]hydrazono]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl] benzenepropanoic acid, was identified as a potent and long-acting TxA2 antagonist. In human platelet rich plasma SQ 35,091 inhibited arachidonic acid (800 microM) and U-46,619 (10 microM) induced aggregation with I50 values of 3 and 12 nM, respectively. In contrast, no inhibition of ADP (20 microM) induced aggregation was observed at greater than 1000 microM. Receptor binding studies with [3H]-SQ 29,548 showed SQ 35,091 was a competitive antagonist with a Kd value of 1.0 +/- 0.1 nM in human platelet membranes. In vivo SQ 35,091 (0.2 mg/kg po) showed extended protection (T50 = 16 h) from U-46,619 (2 mg/kg iv) induced death in mice. These compounds have for the first time demonstrated that a metabolically stable interphenylene alpha-sidechain can be introduced into a prostanoid-like series of TxA2 antagonists with the maintainance of potent antagonistic activity.
Misra
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Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
Brown
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BR
Han
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WC
Harris
D N
DN
Hedberg
A
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Webb
M L
ML
Hall
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D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors; D001792:Blood Platelets / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002462:Cell Membrane / Q000187:drug effects; D005231:Fatty Acids, Unsaturated; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D012664:Semicarbazones / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*
D001095:Arachidonic Acids; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D012664:Semicarbazones; C070945:SQ 35091; D016718:Arachidonic Acid; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; C045749:SQ 29548