Discovery of a N'-hydroxyphenylformamidine derivative HET0016 as a potent and selective 20-HETE synthase inhibitor.
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.
Sato
M
M
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Saitama, Saitama 330-8530, Japan.
Ishii
T
T
Kobayashi-Matsunaga
Y
Y
Amada
H
H
Taniguchi
K
K
Miyata
N
N
Kameo
K
K
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
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