HET0016, a potent and selective inhibitor of 20‐HETE synthesizing enzyme

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 IC50 value averaged 35±4 nM, whereas the IC50 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 IC50 value of 8.9±2.7 nM. Higher concentrations of HET0016 also inhibited the CYP2C9, CYP2D6 and CYP3A4‐catalysed substrates oxidation with IC50 values of 3300, 83,900 and 71,000 nM. The IC50 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. British Journal of Pharmacology (2001) 133, 325–329; doi:10.1038/sj.bjp.0704101