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

Type I and type II steroid 5 alpha-reductases (5 alpha-R) catalyze the conv ersion of testosterone (T) to dihydrotestosterone (DHT). LY320236 is a benz oquinolinone (BQ) that inhibits 5 alpha-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 us ed to evaluate the kinetics of 5 alpha-R inhibition by LY320236. Non-linear modeling of experimental data evaluated V-max in the presence or absence o f LY320236. Experimental data modeled to the following equation 1/v = [(In0 c + (Km/[S]))/V(max)Ki][I] + (1/V-max)(1 + Km/[S]) fixing the In0c value eq ual to 1.0 or 0 are consistent with noncompetitive or competitive inhibitio n, respectively. LY320236 is a competitive inhibitor of type I 5 alpha-R (I n0c = 0, Ki = 3.39 +/- 0.38, RMSE = 1.300) and a non-competitive inhibitor of type II 5 alpha-R (In0c = 1, Ki = 29.7 +/- 3.4, RMSE = 0.0592). These da ta 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 act ivity against the two known human 5 alpha-reductase isozymes. LY320236 repr esents a class of non-steroidal 5 alpha-R inhibitors with potential therape utic utility in treating a variety of androgen dependent disorders. (C) 200 0 Elsevier Science Ltd. All rights reserved.