Discovery of a N '-hydroxyphenylformamidine derivative HET0016 as a potentand 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-eicosatet raenoic acid (20-HETE) synthase. The IC50 value of HET0016 for the producti on 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 relations hip revealed that the unsubstituted hydroxyformamidine moiety and the subst ituent at the para-position of the N-hydroxyformamidine moiety are necessar y for the potent activity of HET0016. (C) 2001 Elsevier Science Ltd. All ri ghts reserved.