M. Yamaguchi et al., NOVEL ANTIASTHMATIC AGENTS WITH DUAL ACTIVITIES OF THROMBOXANE A(2) SYNTHETASE INHIBITION AND BRONCHODILATION .2. 4-(3-PYRIDYL)-1(2H)-PHTHALAZINONES, Journal of medicinal chemistry, 36(25), 1993, pp. 4061-4068
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.