title: Pyrazole and isoxazole derivatives as new, potent, and selective 20-hydroxy-5,8,11,14-eicosatetraenoic acid synthase inhibitors.
abstract: In a previous paper, we reported the N-hydroxyformamidine derivative HET0016 as a potent and selective 20-HETE synthase inhibitor. Despite its attraction as a potential therapeutic agent for cerebral diseases, the preparation of an injectable formulation of HET0016 was limited by its poor solubility under neutral conditions and instability under acidic conditions. The instability of HET0016 in acidic conditions is due to the N-hydroxyformamidine moiety, which is considered to be essential for the potent and selective activity seen in our previous study. The activity was maintained when the N-hydroxyformamidine moiety was replaced by an imidazole ring (3a; IC(50) = 5.7 +/- 1.0 nM), but this was associated with a loss of selectivity for cytochrome p450s (CYPs). However, other azole derivatives such as isoxazole derivative 23 (IC(50) value 38 +/- 10 nM) and pyrazole derivative 24 (IC(50) value 23 +/- 12 nM) showed potent and selective activities with improved stability.
authors.affiliation: Medicinal Research Laboratories, Taisho Pharmaceutical Co, Ltd, 403, Yoshino-Cho 1-Chome, Saitama-Shi, Saitama, 330-8530, Japan. toshio.nakamura@po.rd.taisho.co.jp
authors.forename: Toshio
authors.initials: T
authors.lastname: Nakamura
authors.forename: Masakazu
authors.initials: M
authors.lastname: Sato
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kakinuma
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Miyata
authors.forename: Kazuo
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Kagumi
authors.initials: K
authors.lastname: Bando
authors.forename: Ayumi
authors.initials: A
authors.lastname: Koda
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kameo
mesh_terms: D016718:Arachidonic Acid / Q000737:chemistry; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008190:Lyases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: C480548:5-(4-n-butoxyphenyl)isoxazole; C480549:5-(4-n-butoxyphenyl)pyrazole; D065607:Cytochrome P-450 Enzyme Inhibitors; D007555:Isoxazoles; D011720:Pyrazoles; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D008190:Lyases