title: Discovery of a N'-hydroxyphenylformamidine derivative HET0016 as a potent and selective 20-HETE synthase inhibitor.
abstract: N-(4-Butyl-2-methylphenyl)-N'-hydroxyformamidine (HET0016) was evaluated as the first potent and selective inhibitor of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) synthase. The IC(50) value of HET0016 for the production of 20-HETE from arachidonic acid (AA) by human renal microsomes was 8.9+/-2.7 nM, with over 200 times the selectivity of xenobiotic-metabolizing cytochrome P450 enzymes. An examination of the structure-activity relationship revealed that the unsubstituted hydroxyformamidine moiety and the substituent at the para-position of the N-hydroxyformamidine moiety are necessary for the potent activity of HET0016.
authors.affiliation: Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Saitama, Saitama 330-8530, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.forename: T
authors.initials: T
authors.lastname: Ishii
authors.forename: Y
authors.initials: Y
authors.lastname: Kobayashi-Matsunaga
authors.forename: H
authors.initials: H
authors.lastname: Amada
authors.forename: K
authors.initials: K
authors.lastname: Taniguchi
authors.forename: N
authors.initials: N
authors.lastname: Miyata
authors.forename: K
authors.initials: K
authors.lastname: Kameo
mesh_terms: D000578:Amidines / Q000737:chemistry / Q000494:pharmacology*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000578:Amidines; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D019389:Cytochrome P-450 CYP2D6