Journal of Medicinal Chemistry p. 4061 - 4068 (1993)
Update date:2022-08-04
Topics: Bronchodilation Synthetase Thromboxane A2
Yamaguchi, Masahisa
Kamei, Kenshi
Koga, Takaki
Akima, Michitaka
Maruyama, Akinori
et al.
A series of novel 4-(3-pyridyl)-1(2H)-phthalazinone derivatives which possess dual activities of thromboxane A2 (TXA2) synthetase inhibition and bronchodilation was synthesized, and their pharmacological activities were evaluated.While the length and the bulk of 2-alkyl substituents had no influence on either activity, the 2-substituents with polar groups reduced bronchodilatory activity.Furthermore, we introduced heteroaromatic nuclei into the 4-position of the phthalazinone and found that 1-imidazolyl (13a) and 5-thiazolyl (16b and 16c) derivatives were as active as the parent 3-pyridyl compound 5b.These findings suggest that heteroaromatic nuclei at the 4-position of phthalazinones play a critical role in TXA2 synthetase inhibition.Additionally, the hydrophobicity of the compounds was found to exert a marked influence on bronchodilatory activity.These observations led to the selection of 2-ethyl-4-(3-pyridyl)-1(2H)-phthalazinone (5b) (KK-505) and 2-methyl-4-(5-thiazolyl)-1(2H)-phthalazinone (16b) (KK-562) for further studies.Although their precise mechanism of action remains unclear, this series of novel phthalazinone derivatives represents a new class of antiasthma agents with dual activities.
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