title: Pyrazole derivatives as new potent and selective 20-hydroxy-5,8,11,14-eicosatetraenoic acid synthase inhibitors.
abstract: Improvement of the physical properties of pyrazole derivative 1, which we reported previously as a potent and selective 20-HETE synthase inhibitor (IC(50) 5.7 nM), is described. Introduction of a sufficient substituted-amino group on the side chain enhanced the water-solubility of 1 (0.014 mg/mL at pH 6.8). Among the products, 2-piperazinoethoxy derivatives 3e and 6b showed solubility suitable for injection and potent inhibitory activity toward 20-HETE synthase (IC(50) 21.2 and 14.0 nM, respectively).
authors.affiliation: Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd, 403 Yoshino-Cho 1-Chome, Kita-ku, Saitama-Shi, Saitama 331-9530, Japan. toshio.nakamura@po.rd.taisho.co.jp
authors.forename: Toshio
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kakinuma
authors.forename: Hideaki
authors.initials: H
authors.lastname: Amada
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Miyata
authors.forename: Kazuo
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Ayumi
authors.initials: A
authors.lastname: Koda
authors.forename: Masakazu
authors.initials: M
authors.lastname: Sato
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D020128:Inhibitory Concentration 50; D007668:Kidney; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D011720:Pyrazoles; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid