NOVEL ANTIASTHMATIC AGENTS WITH DUAL ACTIVITIES OF THROMBOXANE A(2) SYNTHETASE INHIBITION AND BRONCHODILATION .1. 2-[2-(1-IMIDAZOLYL)ALKYL]-1(2H)-PHTHALAZINONES
M. Yamaguchi et al., NOVEL ANTIASTHMATIC AGENTS WITH DUAL ACTIVITIES OF THROMBOXANE A(2) SYNTHETASE INHIBITION AND BRONCHODILATION .1. 2-[2-(1-IMIDAZOLYL)ALKYL]-1(2H)-PHTHALAZINONES, Journal of medicinal chemistry, 36(25), 1993, pp. 4052-4060
A number of 4-substituted -[omega-(1-imidazolyl)allryl]-1(2H)-phthalaz
inones were synthesized in order to develop agents possessing both thr
omboxane Az synthetase inhibitory and bronchodilatory activities. The
pharmacological evaluation of these compounds disclosed that they have
both activities to various extents. Both activities were slightly dep
endent on the length of the 2-substituents and largely affected by the
nature of the 4-substituents. Compounds bearing phenyl and thienyl gr
oups exhibited relatively high and well-rounded activities. Among thes
e compounds, 12j and 15f were found to be the most effective agents ha
ving well-rounded activities in vitro and in vivo. Introduction of a c
arboxyl group reduced both activities contrary to our expectation. 4-(
3-Pyridyl)phthalazinone 18b was of particular interest because of unex
pectedly high in vivo activities in spite of an absence of significant
in vitro activities.