Novel 19-(cyclopropylamino)-androst-4-en-3,17-dione: a mechanism-based inhibitor of aromatase.

The novel 19-(cyclopropylamino)-androst-4-en-3,17-dione (5, CPA), a mechanism-based inhibitor of aromatase has been synthesized from the 10 beta-aldehyde intermediate (2). The key reaction was the trifluoroacetic acid-catalysed condensation of 2 with cyclopropylamine in refluxing toluene to give the 19-cyclopropylimine (3). Enzyme inhibition studies show that CPA is a time-dependent, irreversible inhibitor of human placental microsomal aromatase (Ki = 92 +/- = 2 nM). The inactivation of aromatase by CPA was NADPH-dependent and was protected by the presence of substrate testosterone (20 microns). In addition, the inactivation was not affected by the nucleophile, L-cysteine (0.5 mM), suggesting retention of the inhibitor in the enzyme's active site during the inactivation process.