Effects of novel 17-azolyl compounds on androgen synthesis in vitro and in vivo

• Published in: The Journal of steroid biochemistry and molecular biology 1999-12, Vol.71 (3), p.145-152
• Main Authors: Nnane, I.P., Njar, V.C.O., Liu, Y., Lu, Q., Brodie, A.M.H.
• Format: Article
• Language: English
• Subjects: 17-Azolyl steroids; 17α-hydroxylase/C 17,20-Lyase; 5α-Reductase; Androgens; Androgens - biosynthesis; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Azoles - chemistry; Azoles - pharmacology; Biological and medical sciences; Dihydrotestosterone - blood; Dihydrotestosterone - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Genitalia, Male - drug effects; Genitalia, Male - metabolism; Gynecology. Andrology. Obstetrics; Humans; In Vitro Techniques; Kinetics; Male; Male genital diseases; Medical sciences; Prostate - drug effects; Prostate - metabolism; Prostate cancer; Prostatic Neoplasms - drug therapy; Rats; Rats, Sprague-Dawley; Steroid 17-alpha-Hydroxylase - antagonists & inhibitors; Steroids - chemistry; Steroids - pharmacology; Testis - drug effects; Testis - metabolism; Testosterone - blood; Testosterone - metabolism; Tumors
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/S0960-0760(99)00129-6

17-Azolyl steroids were synthesized and evaluated as inhibitors of androgen synthesis in vitro and in vivo. Several of the novel compounds exhibit potent noncompetitive inhibition of human 17α-hydroxylase/C 17,20-lyase with IC 50 values ranging from 7 to 90 nM, and K i values from 1.2 to 41 nM. VN/85-1 and VN/108-1 were the most potent inhibitors against this enzyme with IC 50 value of 8 nM ( K i of 1.2 nM) and 7 nM ( K i of 1.9 nM), respectively. VN/107-1, VN/108-1 and VN/109-1 also showed moderate inhibition of 5α-reductase in human prostatic microsomes. Normal adult male rats were treated with these novel 17-azolyl steroidal compounds at a dose level of 50 mg/kg, s.c., for 14 consecutive days, sacrificed 1–2 h after the last administered dose and blood, prostate and other tissues were collected. The organs were weighed and tissue concentrations of testosterone (T) and dihydrotestosterone (DHT) were measured. Tissue T levels were significantly ( p