NOVEL ANTIASTHMATIC AGENTS WITH DUAL ACTIVITIES OF THROMBOXANE A(2) SYNTHETASE INHIBITION AND BRONCHODILATION .2. 4-(3-PYRIDYL)-1(2H)-PHTHALAZINONES

A series of novel 4-(3-pyridyl)-1(2H)-phthalazinone derivatives which possess dual activities of thromboxane A(2) (TXA(2)) synthetase inhibition and bronchodilation was synthesized, and their pharmacological activities were evaluated. While the length and the built 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 Li-position of phthalazinones play a critical role in TXA(2) 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.