title: Kinetic analysis of LY320236: competitive inhibitor of type I and non-competitive inhibitor of type II human steroid 5alpha-reductase.
abstract: Type I and type II steroid 5alpha-reductases (5alpha-R) catalyze the conversion of testosterone (T) to dihydrotestosterone (DHT). LY320236 is a benzoquinolinone (BQ) that inhibits 5alpha-R activity in human scalp skin (Ki(typeI)=28.7+/-1.87 nM) and prostatic homogenates (Ki(typeII)=10.6+/-4.5 nM). Lineweaver-Burk, Dixon, and non-linear analysis methods were used to evaluate the kinetics of 5alpha-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 1v=+ 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 5alpha-R (In0c=0, Ki=3.39+/-0.38, RMSE = 1.300) and a non-competitive inhibitor of type II 5alpha-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 5alpha-reductase isozymes. LY320236 represents a class of non-steroidal 5alpha-R inhibitors with potential therapeutic utility in treating a variety of androgen dependent disorders.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: McNulty
authors.forename: J E
authors.initials: JE
authors.lastname: Audia
authors.forename: K G
authors.initials: KG
authors.lastname: Bemis
authors.forename: R L
authors.initials: RL
authors.lastname: Goode
authors.forename: V P
authors.initials: VP
authors.lastname: Rocco
authors.forename: B L
authors.initials: BL
authors.lastname: Neubauer
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000145:classification / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D000730:Androstadienes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001667:Binding, Competitive; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000145:classification / Q000378:metabolism; D007700:Kinetics; D008297:Male; D011467:Prostate / Q000201:enzymology; D012535:Scalp / Q000201:enzymology; D013816:Thermodynamics
chemical_list: D058891:5-alpha Reductase Inhibitors; D000730:Androstadienes; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C101585:LY 306089; C072547:epristeride; C407322:Izonsteride; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase