Chemical Mechanism of the Covalent Modification of 5-Alpha-Reductases by Finasteride as Probed by Secondary Tritium Isotope Effects

This study examines the chemical mechanism of the covalent modification of 5-alpha-reductases by finasteride. The study suggests a two-step mechanism involving a high barrier addition of the attacking nucleophile at C-1, followed by a low barrier protonation at C-2. The proposed mechanism has implications for the design of novel covalent inhibitors for use as pharmaceutics. The study also notes that the partitioning of the activated intermediate, which occurs in the mechanism-based inhibition, undermines the potency of the inhibitor and possibly causes adverse effects in vivo.