Substituted 6-(1-pyrrolidine)quinolin-2(1H)-ones as novel selective androgen receptor modulators.
The androgen receptor is a ligand inducible transcription factor that is involved in a broad range of physiological functions. Here we describe the discovery of a new class of orally available selective androgen receptor modulators. The lead compound, 6-[(2R,5R)-2-methyl-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]-4-trifluoromethylquinolin-2(1H)-one (6a), showed excellent anabolic activity in muscle with reduced effect on the prostate in a rat model of hypogonadism. The compound also improved bone strength in a rat model of post-menopausal osteoporosis.
Martinborough
Esther
E
Discovery Research, Ligand Pharmaceuticals Inc., 10275 Science Center Drive, San Diego, California 92121, USA.
Shen
Yixing
Y
Oeveren
Arjan van
Av
Long
Yun Oliver
YO
Lau
Thomas L S
TL
Marschke
Keith B
KB
Chang
William Y
WY
López
Francisco J
FJ
Vajda
Eric G
EG
Rix
Peter J
PJ
Viveros
O Humberto
OH
Negro-Vilar
Andrés
A
Zhi
Lin
L
D000284:Administration, Oral; D045930:Anabolic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000818:Animals; D001682:Biological Availability; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D007006:Hypogonadism / Q000188:drug therapy / Q000473:pathology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy; D011467:Prostate / Q000187:drug effects; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C524268:6-(2-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-4-trifluoromethylquinolin-2(1H)-one; D045930:Anabolic Agents; D059002:Androgen Receptor Antagonists; D000728:Androgens; D050071:Bone Density Conservation Agents; D011759:Pyrrolidines; D011804:Quinolines; D015363:Quinolones