Discovery of the Selective Androgen Receptor Modulator MK-0773 Using a Rational Development Strategy Based on Differential Transcriptional Requirements for Androgenic Anabolism Versus Reproductive Physiology

被引：43

作者：

Schmidt, Azriel ^{[1
]}

Kimmel, Donald B. ^{[1
]}

Bai, Chang ^{[1
]}

Scafonas, Angela ^{[1
]}

Rutledge, SuJane ^{[1
]}

Vogel, Robert L. ^{[1
]}

McElwee-Witmer, Sheila ^{[1
]}

Chen, Fang ^{[1
]}

Nantermet, Pascale V. ^{[1
]}

Kasparcova, Viera ^{[1
]}

Leu, Chih-tai ^{[1
]}

Zhang, Hai-Zhuan ^{[1
]}

Duggan, Mark E. ^{[2
]}

Gentile, Michael A. ^{[1
]}

Hodor, Paul ^{[4
]}

Pennypacker, Brenda ^{[1
]}

Masarachia, Patricia ^{[1
]}

Opas, Evan E. ^{[1
]}

Adamski, Sharon A. ^{[1
]}

Cusick, Tara E. ^{[1
]}

Wang, Jiabing ^{[2
]}

Mitchell, Helen J. ^{[2
]}

Kim, Yuntae ^{[2
]}

Prueksaritanont, Thomayant ^{[3
]}

Perkins, James J. ^{[2
]}

Meissner, Robert S. ^{[2
]}

Hartman, George D. ^{[2
]}

Freedman, Leonard P. ^{[2
]}

Harada, Shun-ichi ^{[1
]}

Ray, William J. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Mol Endocrinol, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Drug Metab, West Point, PA 19486 USA

[4] Merck Res Labs, Dept Mol Profiling, West Point, PA 19486 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2010年 / 285卷 / 22期

关键词：

LEAN BODY-MASS; POSTMENOPAUSAL WOMEN; GENETIC PATHWAYS; MALE RATS; TESTOSTERONE; PROSTATE; BONE; INSENSITIVITY; EXPRESSION; MUTATIONS;

D O I：

10.1074/jbc.M109.099002

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40-80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs.

引用

页码：17054 / 17064

页数：11