Novel series of potent, nonsteroidal, selective androgen receptor modulators based on 7H-[1,4]oxazino[3,2-g]quinolin-7-ones.
Recent interest in orally available androgens has fueled the search for new androgens for use in hormone replacement therapy and as anabolic agents. In pursuit of this, we have discovered a series of novel androgen receptor modulators derived from 7H-[1,4]oxazino[3,2-g]quinolin-7-ones. These compounds were synthesized and evaluated in competitive binding assays and an androgen receptor transcriptional activation assay. A number of compounds from the series demonstrated single-digit nanomolar agonist activity in vitro. In addition, lead compound (R)-16e was orally active in established rodent models that measure androgenic and anabolic properties of these agents. In this assay, (R)-16e demonstrated full efficacy in muscle and only partially stimulated the prostate at 100 mg/kg. These data suggest that these compounds may be utilized as selective androgen receptor modulators or SARMs. This series represents a novel class of compounds for use in androgen replacement therapy.
Higuchi
Robert I
RI
Discovery Research, Ligand Pharmaceuticals, Inc., 10275 Science Center Drive, San Diego, California 92121, USA. rhiguchi@ligand.com
Arienti
Kristen L
KL
López
Francisco J
FJ
Mani
Neelakhanda S
NS
Mais
Dale E
DE
Caferro
Thomas R
TR
Long
Yun Oliver
YO
Jones
Todd K
TK
Edwards
James P
JP
Zhi
Lin
L
Schrader
William T
WT
Negro-Vilar
Andrés
A
Marschke
Keith B
KB
D045930:Anabolic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000728:Androgens; D000818:Animals; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011467:Prostate / Q000033:anatomy & histology / Q000187:drug effects; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects
C520860:1,2,3,6-tetrahydro-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-(1,4)oxazino(3,2-g)quinolin-7-one; D045930:Anabolic Agents; D000728:Androgens; D010078:Oxazines; D015363:Quinolones; D011944:Receptors, Androgen