title: Thromboxane modulating agents. 3. 1H-imidazol-1-ylalkyl- and 3-pyridinylalkyl-substituted 3-[2-[(arylsulfonyl)amino]ethyl]benzenepropanoic acid derivatives as dual thromboxane synthase inhibitor/thromboxane receptor antagonists.
abstract: The design of a series of dual thromboxane synthase inhibitor/thromboxane receptor antagonists based on a 3-[2-[(arylsulfonyl)amino]ethyl]benzenepropanoic acid thromboxane receptor antagonist template is described. Introduction of a 5-(1H-imidazol-1-ylmethyl), a 5-(3-pyridinyl-methyl), or a 5-(3-pyridinyloxy) substituent leads to dual agents with thromboxane synthase inhibitory activity comparable with that of dazmegrel (7). In addition, 3-pyridinylalkyl substituents also make a significant contribution to thromboxane receptor binding. Oral administration of compound 74 (5 mg/kg) to conscious dogs produces long-lasting thromboxane synthase inhibition and thromboxane receptor blockade as measured by inhibition of U46619-induced platelet aggregation ex vivo.
authors.affiliation: Pfizer Central Research, Sandwich, Kent, U.K.
authors.forename: R P
authors.initials: RP
authors.lastname: Dickinson
authors.forename: K N
authors.initials: KN
authors.lastname: Dack
authors.forename: C J
authors.initials: CJ
authors.lastname: Long
authors.forename: J
authors.initials: J
authors.lastname: Steele
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008861:Microsomes / Q000201:enzymology; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000819:agonists / Q000097:blood / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D010666:Phenylpropionates; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D017482:Receptors, Thromboxane; D013931:Thromboxanes; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013930:Thromboxane-A Synthase