LY191704 inhibits type I steroid 5 alpha-reductase in human scalp.
Conversion of testosterone to dihydrotestosterone (DHT) has been demonstrated to be catalyzed by two isoforms of steroid 5 alpha-reductase, designated types I and II. Although several classes of steroid-based inhibitors of the type II isoform have been identified, these agents have not demonstrated highly selective pharmacological activity against human type I 5 alpha-reductase. LY191704 is representative of a series of nonsteroidal agents that have potent [apparent inhibitory constant (Ki) = 11.3 nM] inhibitory activity in human scalp skin homogenates (pH 7.5), a source of type I 5 alpha-reductase. [3H]-DHT production in the presence and absence of LY191704 is consistent with a noncompetitive mode of inhibition. In human prostatic homogenates (pH 5.5), a source of type II 5 alpha-reductase, LY191704 is virtually inactive as an inhibitor [concentration of inhibitor producing 50% inhibition of enzymatic activity (IC50) > 1,000 nM] of [3H]-DHT formation. LY191704 does not inhibit the type I or type II isoforms of rat 5 alpha-reductase, nor does the compound compete for binding to the murine androgen receptor expressed in SF9 cells using a baculo virus expression system. The benzoquinolinones, as exemplified by LY191704, possess exquisite pharmacological selectivity and provide a tool to understand the role of human type I 5 alpha-reductase in normal and pathophysiological states. These agents may also find clinical utility in treating androgen-dependent dermatological conditions.
Neubauer
B L
BL
Lilly Research Laboratories, Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. neubauer_blake_l@lilly.com
Gray
H M
HM
Hanke
C W
CW
Hirsch
K S
KS
Hsiao
K C
KC
Jones
C D
CD
Kumar
M V
MV
Lawhorn
D E
DE
Lindzey
J
J
McQuaid
L
L
Tindall
D J
DJ
Toomey
R E
RE
Yao
R C
RC
Audia
J E
JE
D058891:5-alpha Reductase Inhibitors; D000818:Animals; D001667:Binding, Competitive; D013196:Dihydrotestosterone / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D009994:Osmolar Concentration; D015363:Quinolones / Q000378:metabolism / Q000494:pharmacology*; D012535:Scalp / Q000201:enzymology*
D058891:5-alpha Reductase Inhibitors; D007527:Isoenzymes; D015363:Quinolones; D013196:Dihydrotestosterone; C081531:8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinolin-3(2H)-one