On the bioisosteric potential of diazines: diazine analogues of the combined thromboxane A2 receptor antagonist and synthetase inhibitor Ridogrel.

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Heinisch G, Holzer W, Kunz F, Langer T, Lukavsky P, Pechlaner C, Weissenberger H

On the bioisosteric potential of diazines: diazine analogues of the combined thromboxane A2 receptor antagonist and synthetase inhibitor Ridogrel.

J Med Chem. 1996 Sep 27;39(20):4058-64.

PubMed ID

8831771 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Ridogrel	Thromboxane A2 receptor	Protein	Humans	Yes	Antagonist	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Ridogrel	Thromboxane A2 receptor	IC 50 (nM)	1700	N/A	N/A	Details
Ridogrel	Thromboxane-A synthase	IC 50 (nM)	7	N/A	N/A	Details