Novel Antiasthmatic Agents with Dual Activities of Thromboxane A2 Synthetase Inhibition and Bronchodilation. 2. 4-(3-Pyridyl)-1(2H)-phthalazinones

Article abstract of DOI:10.1021/jm00077a009

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.