Potent, nonsteroidal selective androgen receptor modulators (SARMs) based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones.
A series of androgen receptor modulators based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones was synthesized and evaluated in an androgen receptor transcriptional activation assay. The most potent analogues from the series exhibited single-digit nanomolar potency in vitro. Compound 18h demonstrated full efficacy in the maintenance of muscle weight, at 10 mg/kg, with reduced activity in prostate weight in an in vivo model of androgen action.
Higuchi
Robert I
RI
Discovery Research, Ligand Pharmaceuticals, 10275 Science Center Drive, San Diego, CA 92121, USA. rhiguchi@ligand.com
Thompson
Anthony W
AW
Chen
Jyun-Hung
JH
Caferro
Thomas R
TR
Cummings
Marquis L
ML
Deckhut
Charlotte P
CP
Adams
Mark E
ME
Tegley
Christopher M
CM
Edwards
James P
JP
López
Francisco J
FJ
Kallel
E Adam
EA
Karanewsky
Donald S
DS
Schrader
William T
WT
Marschke
Keith B
KB
Zhi
Lin
L
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007202:Indicators and Reagents; D008297:Male; D008958:Models, Molecular; D009919:Orchiectomy; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D011944:Receptors, Androgen / Q000737:chemistry / Q000187:drug effects*; D011980:Receptors, Progesterone / Q000737:chemistry / Q000187:drug effects; D011986:Receptors, Somatotropin / Q000737:chemistry / Q000187:drug effects; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000097:blood
D007202:Indicators and Reagents; D010078:Oxazines; D015363:Quinolones; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; D011986:Receptors, Somatotropin; D013739:Testosterone
J Clin Endocrinol Metab. 2005 Feb;90(2):678-88
15562020
N Engl J Med. 1996 Mar 14;334(11):707-14
8594431
J Med Chem. 2006 Oct 19;49(21):6143-6
17034117
Bioorg Med Chem Lett. 2006 Nov 15;16(22):5763-6
16959487
Proc Soc Exp Biol Med. 1953 May;83(1):175-80
13064212
J Med Chem. 1995 Dec 8;38(25):4855-74
8523397
J Clin Endocrinol Metab. 1997 Feb;82(2):407-13
9024227
J Med Chem. 2006 Dec 28;49(26):7596-9
17181141
J Med Chem. 1998 Feb 12;41(4):623-39
9484511
J Clin Endocrinol Metab. 1999 Oct;84(10):3459-62
10522980
J Med Chem. 2007 May 17;50(10):2486-96
17439112
J Med Chem. 2004 Feb 12;47(4):993-8
14761201
Acta Crystallogr Sect F Struct Biol Cryst Commun. 2006 Nov 1;62(Pt 11):1067-71
17077481
Biol Pharm Bull. 2003 Nov;26(11):1563-9
14600402
Clin Endocrinol (Oxf). 2003 Jun;58(6):691-5
12780744