The potent and selective inhibition of estrogen production by non-steroidal aromatase inhibitor, YM511

• Published in: The Journal of steroid biochemistry and molecular biology Vol. 54; no. 5; pp. 265 - 271
• Main Authors: Kudoh, Masafumi, Susaki, Yoko, Ideyama, Yukitaka, Nanya, Taiki, Okada, Minoru, Shikama, Hisataka, Fujikura, Takashi
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.09.1995; Elsevier Science
• Subjects: Animals; Aromatase Inhibitors; Biological and medical sciences; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Estrogen Antagonists - pharmacology; Estrogens - analysis; Estrogens - blood; Female; Hormones. Endocrine system; Humans; Medical sciences; Microsomes - drug effects; Organ Size - drug effects; Ovariectomy; Ovary - drug effects; Pharmacology. Drug treatments; Placenta - drug effects; Pregnancy; Rats; Rats, Wistar; Triazoles - pharmacology; Human; Ovary; Placenta; Enzyme; Animal; Female genital system; Estrogen; Enzyme inhibitor; Steroidogenesis; Estrogen synthase; Sex steroid hormone; Estradiol
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/0960-0760(95)00136-N

YM511 inhibited aromatase activities in microsomes from rat ovary and human placenta competitively (IC 50s: 0.4 and 0.12 nM, respectively). YM511 was about 3 times more potent than other aromatase inhibitors, such as CGS 16949A, CGS 20267 and R 76713. YM511 decreased the contents of estradiol stimulated by pregnant mare's serum gonadotropin in rat ovary with an ED 50 of 0.002 mg/kg, indicating that YM511 was equipotent to CGS 20267 and 3 times more potent than the other two inhibitors. Serum estradiol levels in female rats were reduced by YM511 at 0.01 mg/kg into the ovariectomized range. YM511 at 1 mg/kg for 2 weeks decreased rat uterine weight to levels comparable to ovariectomy, showing it was 10 times more potent than other inhibitors. But the maximal inhibitory effect of tamoxifen failed to reach ovariectomized level. YM511 slightly inhibited production of other steroid hormones in vitro and in vivo. The IC 50s of YM511 for aldosterone and cortisol production from adrenal cells were from 5500 to 9800 times higher than that for rat ovarian aromatase and 130,000 times higher for testosterone production, indicating that YM511 is a highly specific aromatase inhibitor. The data suggest that YM511 may be a potent and selective agent for suppressing estrogen-dependent action without affecting serum levels of other steroid hormones.