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Hair Loss Study Abstract: LY191704: a selective, nonsteroidal inhibitor of human steroid 5 alpha-reductase
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Title
LY191704: a selective, nonsteroidal inhibitor of human steroid 5 alpha-reductase type 1.
Author
Hirsch KS; Jones CD; Audia JE; Andersson S; McQuaid L; Stamm NB; Neubauer BL; Pennington
P; Toomey RE; Russell DW
Address
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Source
Proc Natl Acad Sci U S A, 1993 Jun 1, 90:11, 5277-81
Abstract
Androgens, in particular dihydrotestosterone (DHT), play a key role in differentiation,
growth, and maintenance of the mammalian prostate. Production of DHT from testosterone is
catalyzed by two distinct membrane-bound steroid 5 alpha-reductase [5 alpha-reductase;
3-oxo-5 alpha-steroid delta 4-dehydrogenase; 3-oxo-5 alpha-steroid:(acceptor) delta
4-oxidoreductase, EC 1.3.99.5] isozymes designated types 1 and 2. Benign prostatic
hyperplasia (BPH), a disease that occurs almost universally in males, is characterized by
obstructive and irritative urinary voiding symptoms and has been associated with an
overproduction of DHT. Recently, steroidal inhibitors of 5 alpha-reductase type 2 have
been used successfully for treatment of BPH. Described here is a nonsteroidal inhibitor of
5 alpha-reductase type 1, LY191704
(8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octaahydro-benzo[f]quinol in-3(2H)-one). This
compound was identified based on its capacity to inhibit 5 alpha-reductase activity in a
human genital skin fibroblast cell line (Hs68). Surprisingly, LY191704 is inactive when
tested in freshly isolated prostate cells obtained from subjects with BPH, whereas
previously described 4-azasteroids are active. LY191704 is, however, a potent inhibitor of
the 5 alpha-reductase activity of BPH cells that have been maintained in culture. Analysis
of human and rat 5 alpha-reductases expressed from transfected cDNAs in simian COS cells
indicates that LY191704 is a specific noncompetitive inhibitor of the human 5
alpha-reductase type 1. Taken together, the results suggest that prostate cells have the
capacity to express both 5 alpha-reductase isozymes and that LY191704 may be useful in
treatment of human endocrine disorders associated with overproduction of DHT by 5
alpha-reductase type 1.
Language of Publication
LA=ENG
Unique Identifier
93281741
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