title: Agents combining thromboxane receptor antagonism with thromboxane synthase inhibition: [[[2-(1H-imidazol-1-yl)ethylidene]amino]oxy]alkanoic acids.
abstract: A new class of compounds combining thromboxane-A2 (TxA2) receptor antagonism and thromboxane synthase inhibition is described. A first series of (E)- and (Z)-[[[2-(1H-imidazol-1-yl)ethylidene]amino]oxy]pentanoic acids showed relevant thromboxane synthase inhibition associated with weak TxA2 receptor antagonism, while a series of (+/-)-(E)-[[[2-(1H-imidazol-1-yl)-3-phenylpropylidene]amino]oxy] pentanoic acids, structurally derived from the former, showed potent and well-balanced dual activity. Structural requirements for significant single and dual activity are discussed. Two close congeners of the latter series, (+/-)-(E)-5-[[[1-cyclohexyl-2-(1H-imidazol-1-yl)-3- phenylpropylidene]amino]oxy]pentanoic acid 23c and its p-fluorophenyl analog 23m, inhibited TxB2 production in vitro, in rat whole blood during clotting, with IC50 of 0.06 and 0.37 microM and antagonized the binding of [3H]SQ 29548 to washed human platelets, with IC50 of 0.08 and 0.02 microM, respectively. These two compounds were selected for further pharmacological evaluation and were shown to antagonize U46619-induced platelet aggregation in human platelet rich plasma with IC50 of 0.30 and 0.44 microM, respectively. They were both orally available, and in particular 23m caused a long lasting ex vivo TxA2 synthase inhibition in the fed rat. The levorotatory enantiomer of 23c, stereospecifically synthesized as a model compound, was found to be more potent than racemic 23c with regard to TxA2 receptor antagonism (IC50 = 0.04 microM) and equivalent to the latter with regard to TxA2 synthase inhibition. A molecular modeling study concerning the levorotatory enantiomer of 23c (S), TxA2, and representative TxA2 antagonists of different classes led to the definition of a putative pharmacophoric model for the TxA2 receptor ligands.
authors.affiliation: Business Unit Therapeutics, Laboratory of Chemistry, Pharmacia-Farmitalia Carlo Erba, Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Cozzi
authors.forename: A
authors.initials: A
authors.lastname: Giordani
authors.forename: M
authors.initials: M
authors.lastname: Menichincheri
authors.forename: A
authors.initials: A
authors.lastname: Pillan
authors.forename: V
authors.initials: V
authors.lastname: Pinciroli
authors.forename: A
authors.initials: A
authors.lastname: Rossi
authors.forename: R
authors.initials: R
authors.lastname: Tonani
authors.forename: D
authors.initials: D
authors.lastname: Volpi
authors.forename: M
authors.initials: M
authors.lastname: Tamburin
authors.forename: R
authors.initials: R
authors.lastname: Ferrario
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001667:Binding, Competitive; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003198:Computer Simulation; D004285:Dogs; D005231:Fatty Acids, Unsaturated; D005343:Fibrinolytic Agents; D006801:Humans; D006834:Hydrazines / Q000097:blood; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D010421:Pentanoic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D005343:Fibrinolytic Agents; D006834:Hydrazines; D007093:Imidazoles; D010421:Pentanoic Acids; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; C087932:FCE 27262; C090032:5-(((1-cyclohexyl-2-(1H-imidazol-1-yl)-3-(4-fluorophenyl)propylidene)amino)oxy)pentanoic acid; D013929:Thromboxane B2; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D013930:Thromboxane-A Synthase