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 inhibi tion and bronchodilation was synthesized, and their pharmacological ac tivities were evaluated. While the length and the built of 2-alkyl sub stituents had no influence on either activity, the 2-substituents with polar groups reduced bronchodilatory activity. Furthermore, we introd uced heteroaromatic nuclei into the 4-position of the phthalazinone an d found that 1-imidazolyl (13a) and 5-thiazolyl (16b and 16c) derivati ves were as active as the parent 3-pyridyl compound 5b. These findings suggest that heteroaromatic nuclei at the Li-position of phthalazinon es play a critical role in TXA(2) synthetase inhibition, Additionally, the hydrophobicity of the compounds was found to exert a marked influ ence on bronchodilatory activity. These observations led to the select ion 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, t his series of novel phthalazinone derivatives represents a new class o f antiasthma agents with dual activities.