title: Synthesis and antiplatelet activity of new imidazole-4-carboxylic acid derivatives.
abstract: 1-Arylalkyl-5-phenylsulfonamino-imidazole-4-carboxylic acid esters and their carboxamides with an additional secondary amino group were synthesized and identified as antiplatelet agents in a low micromolar range (Born-test, inducer collagen). To describe the mechanism of action more precisely the Born-test was carried out as well with ADP, adrenaline or PAF, respectively. In addition, two compounds were investigated for their COX-1 inhibitory activities. Provided the essential structural criteria are met i.e. amide group or ester, sulfonylamino rest, hydrophobic moieties, and a secondary amino function, slight structural modifications are able to shift the pattern of activity among the above platelet receptors. So, the ester 5c exhibits PAF antagonistic activity at IC(50) = 1 microM and COX-1 inhibition (IC(50) = 0.4 microM). The carboxamide 6c shows ADP antagonistic properties (IC(50) = 2 microM). Compound 6g is as well PAF antagonistic (IC(50) = 4 microM) and a COX-1 inhibitor (IC(50) = 1 microM). The derivative 6i shows a strong antiadrenergic (IC(50) = 0.15 microM) and PAF antagonistic (IC(50) = 0.66 microM) effect.
authors.affiliation: Institut für Pharmazie, Freie Universität Berlin, Berlin, Germany. rehiwer@zedat.fu-berlin.de
authors.forename: Klaus
authors.initials: K
authors.lastname: Rehse
authors.forename: Jens
authors.initials: J
authors.lastname: Steege
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D003094:Collagen