title: Non-prostanoid prostacyclin mimetics. 6. Derivatives of 2-[3-[2-(4,5-Diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid modified beta-to the oxazole ring.
abstract: 2-[3-[2-(4,5-Diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid, 1, has been described as a non-prostanoid PGI2 mimetic that demonstrates anti-thrombotic properties of long duration in animal models of thrombosis. The effects of substitution and modification of the carbon beta-to the oxazole heterocycle of 1 were examined and equated with the potency of the compounds as inhibitors of ADP-induced human platelet aggregation in vitro. Potency was sensitive to both the size of the substituent and the identity of the beta-atom. The carbamates 13c-e demonstrated IC50's of 0.28-0.36 microM and were significantly more potent than the progenitor 1, IC50 = 1.2 microM. The ethyl carbamate 13c displaced [3H]-iloprost from platelet membranes in a concentration-dependent fashion that was half maximal at 20 nM, which compares with IC50's of 171 nM for 1 and 39 nM or unlabelled iloprost. Carbamate 13c stimulated platelet adenylate cyclase but the maximal effect was less than that observed for PGI2, identifying 13c as a partial agonist at the platelet PGI2 receptor.
authors.affiliation: Division of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492-7660.
authors.forename: N A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: M J
authors.initials: MJ
authors.lastname: Rosenfeld
authors.forename: A K
authors.initials: AK
authors.lastname: Trehan
authors.forename: J J
authors.initials: JJ
authors.lastname: Wright
authors.forename: C L
authors.initials: CL
authors.lastname: Brassard
authors.forename: J O
authors.initials: JO
authors.lastname: Buchanan
authors.forename: M E
authors.initials: ME
authors.lastname: Federici
authors.forename: J S
authors.initials: JS
authors.lastname: Fleming
authors.forename: M
authors.initials: M
authors.lastname: Gamberdella
authors.forename: K S
authors.initials: KS
authors.lastname: Hartl
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010642:Phenoxyacetates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D010080:Oxazoles; D010642:Phenoxyacetates; D010975:Platelet Aggregation Inhibitors; C080116:BMY 42393; D016285:Iloprost