Bioorganic & Medicinal Chemistry 2000-06-01

Novel imidazolyl and triazolyl substituted biphenyl compounds: synthesis and evaluation as nonsteroidal inhibitors of human 17alpha-hydroxylase-C17, 20-lyase (P450 17).

Y Zhuang, B G Wachall, R W Hartmann

Index: Bioorg. Med. Chem. 8(6) , 1245-52, (2000)

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Abstract

The synthesis of a new series of P450 17 inhibitors is described. The imidazol-1-yl compounds 5 showed strong inhibition of P450 17 rat and especially human enzyme, the most active compounds being 5ax, 5ay and 5bx with IC50 values of 0.17, 0.24 and 0.25 microM, respectively (ketoconazole: 0.74 microM). The 1,2,4-triazol-1-yl compounds 6 were less active, while the 1,2,4-triazol-4-yl compounds 7 were inactive. The title compounds showed little inhibition of P450 arom. The most active P450 17 inhibitors 5ax and 5ay markedly decreased the testosterone plasma concentration of SD rats 2 h after application of 0.019 mmol/kg. After 6 h, 5ay still exhibited a strong effect.