title: 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.
abstract: 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.
authors.affiliation: Department of Molecular Endocrinology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: Azriel
authors.initials: A
authors.lastname: Schmidt
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kimmel
authors.forename: Chang
authors.initials: C
authors.lastname: Bai
authors.forename: Angela
authors.initials: A
authors.lastname: Scafonas
authors.forename: Sujane
authors.initials: S
authors.lastname: Rutledge
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vogel
authors.forename: Sheila
authors.initials: S
authors.lastname: McElwee-Witmer
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.forename: Pascale V
authors.initials: PV
authors.lastname: Nantermet
authors.forename: Viera
authors.initials: V
authors.lastname: Kasparcova
authors.forename: Chih-Tai
authors.initials: CT
authors.lastname: Leu
authors.forename: Hai-Zhuan
authors.initials: HZ
authors.lastname: Zhang
authors.forename: Mark E
authors.initials: ME
authors.lastname: Duggan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gentile
authors.forename: Paul
authors.initials: P
authors.lastname: Hodor
authors.forename: Brenda
authors.initials: B
authors.lastname: Pennypacker
authors.forename: Patricia
authors.initials: P
authors.lastname: Masarachia
authors.forename: Evan E
authors.initials: EE
authors.lastname: Opas
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Adamski
authors.forename: Tara E
authors.initials: TE
authors.lastname: Cusick
authors.forename: Jiabing
authors.initials: J
authors.lastname: Wang
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Mitchell
authors.forename: Yuntae
authors.initials: Y
authors.lastname: Kim
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: James J
authors.initials: JJ
authors.lastname: Perkins
authors.forename: Robert S
authors.initials: RS
authors.lastname: Meissner
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Leonard P
authors.initials: LP
authors.lastname: Freedman
authors.forename: Shun-ichi
authors.initials: S
authors.lastname: Harada
authors.forename: William J
authors.initials: WJ
authors.lastname: Ray
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D001378:Azasteroids / Q000737:chemistry / Q000494:pharmacology*; D019556:COS Cells; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002522:Chlorocebus aethiops; D015195:Drug Design; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008297:Male; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D051381:Rats; D011944:Receptors, Androgen / Q000737:chemistry*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013256:Steroids / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: C550076:3-fluoro-N-(3H-imidazo(4,5-b)pyridin-2-ylmethyl)-1,4a,6a-trimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno(5,4-f)quinoline-7-carboxamide; D000728:Androgens; D001378:Azasteroids; D006727:Hormone Antagonists; D008024:Ligands; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D013256:Steroids