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

• Published in: The journal of clinical endocrinology and metabolism Vol. 81; no. 6; pp. 2055 - 2060
• Main Authors: NEUBAUER, B. L, GRAY, H. M, TINDALL, D. J, TOOMEY, R. E, YAO, R. C, AUDIA, J. E, HANKE, C. W, HIRSCH, K. S, HSIAO, K. C, JONES, C. D, KUMAR, M. V, LAWHORN, D. E, LINDZEY, J, MCQUAID, L
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01-06-1996
• Subjects: 5-alpha Reductase Inhibitors; Animals; Binding, Competitive; Biological and medical sciences; Dihydrotestosterone - metabolism; Humans; Isoenzymes - antagonists & inhibitors; Male; Medical sciences; Mice; Osmolar Concentration; Pharmacology. Drug treatments; Quinolones - metabolism; Quinolones - pharmacology; Scalp - enzymology; Skin, nail, hair, dermoskeleton; Human; Molecular form; Androgen; Enzyme; Enzyme inhibitor; Cholestenone 5α-reductase; In vitro; Biological activity; Testosterone; Chemotherapy; Dihydrotestosterone; Specificity; Treatment; Enzymatic activity; Scalp; Oxidoreductases; Sex steroid hormone; Androgenetic alopecia
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.81.6.2055

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.