Kinetic analysis of LY320236: competitive inhibitor of type I and non-competitive inhibitor of type II human steroid 5α-reductase

Abstract Type I and type II steroid 5α-reductases (5α-R) catalyze the conversion of testosterone (T) to dihydrotestosterone (DHT). LY320236 is a benzoquinolinone (BQ) that inhibits 5α-R activity in human scalp skin ( Ki type I =28.7±1.87 nM) and prostatic homogenates ( Ki type II =10.6±4.5 nM). Lineweaver–Burk, Dixon, and non-linear analysis methods were used to evaluate the kinetics of 5α-R inhibition by LY320236. Non-linear modeling of experimental data evaluated V max in the presence or absence of LY320236. Experimental data modeled to the following equation 1 v = In0c+ Km/ S V max Ki I + 1 V max 1+ Km S fixing the In0c value equal to 1.0 or 0 are consistent with non-competitive or competitive inhibition, respectively. LY320236 is a competitive inhibitor of type I 5α-R ( In0c =0, Ki =3.39±0.38, RMSE = 1.300) and a non-competitive inhibitor of type II 5α-R ( In0c =1, Ki =29.7±3.4, RMSE = 0.0592). These data are in agreement with linear transformation of the data using Lineweaver–Burk and Dixon analyses. These enzyme kinetic data support the contention that the BQ LY320236 is a potent dual inhibitor with differing modes of activity against the two known human 5α-reductase isozymes. LY320236 represents a class of non-steroidal 5α-R inhibitors with potential therapeutic utility in treating a variety of androgen dependent disorders.