title: Novel antiasthmatic agents with dual activities of thromboxane A2 synthetase inhibition and bronchodilation. 2. 4-(3-Pyridyl)-1(2H)-phthalazinones.
abstract: 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.
authors.affiliation: Fuji-gotemba Research Laboratories, Chugai Pharmaceutical Company, Ltd., Shizuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: K
authors.initials: K
authors.lastname: Kamei
authors.forename: T
authors.initials: T
authors.lastname: Koga
authors.forename: M
authors.initials: M
authors.lastname: Akima
authors.forename: A
authors.initials: A
authors.lastname: Maruyama
authors.forename: T
authors.initials: T
authors.lastname: Kuroki
authors.forename: N
authors.initials: N
authors.lastname: Ohi
mesh_terms: D000818:Animals; D001993:Bronchodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D001993:Bronchodilator Agents; D010793:Phthalazines; D011725:Pyridines; D013844:Thiazoles; C084855:2-ethyl-4-(3-pyridyl)-1(2H)-phthalazinone; C084856:2-methyl-4-(5-thiazolyl)-1(2H)-phthalazinone; D013930:Thromboxane-A Synthase