title: On the bioisosteric potential of diazines: diazine analogues of the combined thromboxane A2 receptor antagonist and synthetase inhibitor Ridogrel.
abstract: In this SAR study the bioisosteric potential of diazines in the field of combined antithrombotic thromboxane A2 synthetase inhibitors and receptor antagonists was investigated. In this context, two series of (E)- and (Z)-omega-[[(aryldiazinylmethylene)amino]oxy]alkanoic acids were synthesized of which pentanoic acid derivatives with a 2-pyrazinyl, 4-pyridazinyl, or 5-pyrimidinyl group were found to exhibit this dual activity, while 4-pyrimidinyl as well as 3-pyridazinyl analogues showed only receptor antagonistic activity and 2-pyrimidinyl congeners were inactive. In the series of diazine analogues of Ridogrel (1), replacement of the 3-pyridyl group by a 2-pyrazinyl, 4-pyridazinyl, or 5-pyrimidinyl moiety led to compounds that inhibit thromboxane A2 synthetase in gel-filtered human platelets comparable to 1 (IC50 of 0.006, 0.016, and 0.039 microM, respectively, versus 0.007 microM). Radioligand-binding studies with [3H]SQ 29,548 in washed human platelets revealed that these diazine analogues block the thromboxane A2 receptor with an IC50 of 11, 6.0, and 1.5 microM, respectively. This compares well with the IC50 = 1.7 microM of 1. Finally, testing of inhibition of collagen-induced platelet aggregation in human platelet aggregation in human platelet-rich plasma with 2-pyrazinyl, 4-pyridazinyl, or 5-pyrimidinyl congeners of Ridogrel indicated that these heteroaromatic moieties may serve as bioisosteric substitutes of a 3-pyridyl group in dual-acting antiplatelet agents.
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Innsbruck, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Heinisch
authors.forename: W
authors.initials: W
authors.lastname: Holzer
authors.forename: F
authors.initials: F
authors.lastname: Kunz
authors.forename: T
authors.initials: T
authors.lastname: Langer
authors.forename: P
authors.initials: P
authors.lastname: Lukavsky
authors.forename: C
authors.initials: C
authors.lastname: Pechlaner
authors.forename: H
authors.initials: H
authors.lastname: Weissenberger
mesh_terms: D001792:Blood Platelets / Q000201:enzymology / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003094:Collagen / Q000494:pharmacology; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006801:Humans; D006834:Hydrazines / Q000378:metabolism; D015394:Molecular Structure; D010421:Pentanoic Acids / Q000737:chemistry* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014316:Tritium
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010421:Pentanoic Acids; D010975:Platelet Aggregation Inhibitors; D011719:Pyrazines; D011724:Pyridazines; D011725:Pyridines; D011743:Pyrimidines; D017482:Receptors, Thromboxane; D014316:Tritium; C045749:SQ 29548; D003094:Collagen; D013930:Thromboxane-A Synthase; C060219:ridogrel