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Journal of Clinical Endocrinology & Metabolism, Vol 81, 2055-2060, Copyright © 1996 by Endocrine Society

ARTICLES

LY191704 inhibits type I steroid 5 alpha-reductase in human scalp

BL Neubauer, HM Gray, CW Hanke, KS Hirsch, KC Hsiao, CD Jones, MV Kumar, DE Lawhorn, J Lindzey, L McQuaid, DJ Tindall, RE Toomey, RC Yao and JE Audia
Lilly Research Laboratories, Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. neubauer_blake_l@lilly.com

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.


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[Abstract] [Full Text] [PDF]


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