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

Blake Lee Neubauer, Howard M. Gray, C. William Hanke, Kenneth S. Hirsch, Kenneth C. Hsiao, C. David Jones, M. Vijay Kumar, David E. Lawhorn, Jonathon Lindzey, Loretta Mcquaid, Donald J. Tindall, Richard E. Toomey, Raymond C. Yao, James E. Audia

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Conversion of testosterone to dihydrotestosterone (DHT) has been demonstrated to be catalyzed by two isoforms of steroid 5α-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 5α-reductase. LY191704 is representative of a series of nonsteroidal agents that have potent [apparent inhibitory constant (K(i)) = 11.3 nM] inhibitory activity in human scalp skin homogenates (pH 7.5), a source of type I 5α- 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 5α-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 5α- reductase, nor does the compound compete for binding to the murine androgen receptor expressed in SF9 cells using a baculovirus expression system. The benzoquinolinones, as exemplified by LY191704, possess exquisite pharmacological selectivity and provide a tool to understand the role of human type I 5α-reductase in normal and pathophysiological states. These agents may also find clinical utility in treating androgen-dependent dermatological conditions.

Original languageEnglish (US)
Pages (from-to)2055-2060
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume81
Issue number6
DOIs
StatePublished - 1996

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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