LY207320 (6-methylene-4-pregnene-3,20-dione) inhibits testosterone biosynthesis, androgen uptake, 5 alpha-reductase, and produces prostatic regression in male rats.
LY207320 is an in vitro inhibitor (estimated IC50 = 0.06 microM) of steroid 5 alpha-reductase that catalyzes the conversion of testosterone (T) to dihydrotestosterone (DHT). In contrast, LY207320 was only moderately active against rat prostatic 5 alpha-reductase in vivo (32% inhibition at 50.0 mg/kg single dose). LY207320 did, however, inhibit the in vivo uptake of [3H]-T by the prostate. The antiprostatic and endocrine effects of this agent were evaluated following daily (21 days) administration to castrated, androgen-supplemented castrate, and intact rats. LY207320, which has modest progestational competitive binding activity, does not bind to rat prostatic androgen or uterine estrogen cytosolic receptors. In the castrated male rat, subcutaneously (s.c.) administered LY207320 had no androgen agonist activity, as evidenced by a lack of accessory sex organ weight gains. Administration of s.c. LY207320 to intact rats for 21 days at doses greater than 5.0 mg/kg-day produced significant (P < 0.05) reductions of seminal vesicle and ventral prostatic weights (maximal regression = -65% and -40% from control values, respectively at 50.0 mg/kg-day). The compound had no regressive activity on male accessory sex organs when administered orally. LY207320 did not alter circulating prolactin, LH, or corticosterone levels, but at high doses (> or = 50.0 mg/kg-day), lowered circulating T[-67% from intact control levels (P < 0.05)]. Histological analysis of the rat ventral prostates (RVPs) in LY207320-treated rats was consistent with an androgen-deprived state. Decreased circulating androgens and prostatic regression are associated with inhibition of testicular 17 alpha-hydroxy/C17,20-lyase enzyme activity (IC50 = 0.06 microM). These findings support the contention that LY207320 is a physiological antagonist of androgen action in male rats, and that its effects are mediated primarily through inhibition of testicular androgen production rather than accessory sex organ 5 alpha-reductase.
Neubauer
B L
BL
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
Best
K L
KL
Blohm
T R
TR
Gates
C
C
Goode
R L
RL
Hirsch
K S
KS
Laughlin
M E
ME
Petrow
V
V
Smalstig
E B
EB
Stamm
N B
NB
D000446:Aldehyde-Lyases / Q000187:drug effects; D000726:Androgen Antagonists; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D042944:Cholestenone 5 alpha-Reductase; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D008297:Male; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011374:Progesterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013254:Steroid 17-alpha-Hydroxylase; D013739:Testosterone / Q000037:antagonists & inhibitors*
D000726:Androgen Antagonists; D000728:Androgens; C036790:6-methylene-4-pregnene-3,20-dione; D013739:Testosterone; D011374:Progesterone; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D013254:Steroid 17-alpha-Hydroxylase; D042944:Cholestenone 5 alpha-Reductase; D000446:Aldehyde-Lyases