title: HET0016, a potent and selective inhibitor of 20-HETE synthesizing enzyme.
abstract: The present study examined the inhibitory effects of N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016) on the renal metabolism of arachidonic acid by cytochrome P450 (CYP) enzymes. HET0016 exhibited a high degree of selectivity in inhibiting the formation of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) in rat renal microsomes. The IC(50) value averaged 35+/-4 nM, whereas the IC(50) value for inhibition of the formation of epoxyeicosatrienoic acids by HET0016 averaged 2800+/-300 nM. In human renal microsomes, HET0016 potently inhibited the formation of 20-HETE with an IC(50) value of 8.9+/-2.7 nM. Higher concentrations of HET0016 also inhibited the CYP2C9, CYP2D6 and CYP3A4-catalysed substrates oxidation with IC(50) values of 3300, 83,900 and 71,000 nM. The IC(50) value for HET0016 on cyclo-oxygenase activity was 2300 nM. These results indicate that HET0016 is a potent and selective inhibitor of CYP enzymes responsible for the formation of 20-HETE in man and rat.
authors.affiliation: Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Yoshino-cho, Ohmiya, Saitama 330-8530, Japan. s14307@ccm.taisho.co.jp
authors.forename: N
authors.initials: N
authors.lastname: Miyata
authors.forename: K
authors.initials: K
authors.lastname: Taniguchi
authors.forename: T
authors.initials: T
authors.lastname: Seki
authors.forename: T
authors.initials: T
authors.lastname: Ishimoto
authors.forename: M
authors.initials: M
authors.lastname: Sato-Watanabe
authors.forename: Y
authors.initials: Y
authors.lastname: Yasuda
authors.forename: M
authors.initials: M
authors.lastname: Doi
authors.forename: S
authors.initials: S
authors.lastname: Kametani
authors.forename: Y
authors.initials: Y
authors.lastname: Tomishima
authors.forename: T
authors.initials: T
authors.lastname: Ueki
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.forename: K
authors.initials: K
authors.lastname: Kameo
mesh_terms: D000578:Amidines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000578:Amidines; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; D016718:Arachidonic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D039181:Steroid 16-alpha-Hydroxylase; C510163:CYP3A4 protein, human