Enzyme Inactivation by Potential Metabolites of An Aromatase-Activated Inhibitor (Mdl 18,962)

Abstract

MDL 18,962, 19-acetylenic androstenedione, is an enzyme-activated inhibitor of estrogen biosynthesis which is in Phase I clinical evaluations as a potential therapeutic agent for estrogen-dependent cancers. 19-Acetylenic analogs corresponding to the major metbolites of androstenedione were synthesized as potential metabolites of MDL 18,962. These compounds were 19-acetylenic testosterone, the product of 17β-hydroxy steroid oxidoreductase, 6β-hydroxy- and 6-oxo-19-acetylenic androstenedione, products of P₄₅₀ steroid 6β-hydroxylase and alcohol dehydrogenase, respectively. All of these analogs showed time-dependent inactivation of human placental aromatase activity. The time-dependent K_i and t_1/2 at infinite inhibitor concentration (₅₀) were 4.3 nM, 12.0 min for MDL 18,962; 28 nM, 7.8 min for 17-hydroxy analog; 13nM, 37min for 6β-hydroxy analog; and 167nM, 6.1min for the 6-oxo analog. The 19-acetylenic testosterone, a confirmed metabolite from primate studies, was 25% as efficient as MDL 18,962 for aromatase inactivation, while 6β-hydroxy- and 6-oxo analogs were 11% and 5%, respectively as efficient as their parent compound. These data indicate that first-pass metabolism of MDL 18,962 does not cause an obligatory loss of time-dependent inhibition of human aromatase activity.

Key Words: :

• Aromatase Inhibition
• MDL 18,962
• Estrogen Biosynthesis
• P₄₅₀ Hydroxylation
• steroid 17β-Dehydrogenase