Synthesis, structure-activity relationships, and characterization of novel nonsteroidal and selective androgen receptor modulators.
Herein we describe the discovery of ACP-105 (1), a novel and potent nonsteroidal selective androgen receptor modulator (SARM) with partial agonist activity relative to the natural androgen testosterone. Compound 1 was developed from a series of compounds found in a HTS screen using the receptor selection and amplification technology (R-SAT). In vivo, 1 improved anabolic parameters in a 2-week chronic study in castrated male rats. In addition to compound 1, a number of potent antiandrogens were discovered from the same series of compounds whereof one compound, 13, had antagonist activity at the AR T877A mutant involved in prostate cancer.
ACADIA Pharmaceuticals AB, Medeon Science Park, S-205 12 Malmo, Sweden.
Nathalie
N
Schlienger
Birgitte W
BW
Lund
Jan
J
Pawlas
Fabrizio
F
Badalassi
Fabio
F
Bertozzi
Rasmus
R
Lewinsky
Alma
A
Fejzic
Mikkel B
MB
Thygesen
Ali
A
Tabatabaei
Stefania Risso
SR
Bradley
Luis R
LR
Gardell
Fabrice
F
Piu
Roger
R
Olsson
D000284:Administration, Oral; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000818:Animals; D053961:Azabicyclo Compounds / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009154:Mutation; D041681:NIH 3T3 Cells; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics; D051381:Rats; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D043343:Testosterone Propionate / Q000494:pharmacology
C545686:2-chloro-4-(3-hydroxy-3-methyl-8-azabicyclo(3.2.1)oct-8-yl)-3-methylbenzonitrile; D059002:Androgen Receptor Antagonists; D000728:Androgens; D053961:Azabicyclo Compounds; D008024:Ligands; D011944:Receptors, Androgen; D043343:Testosterone Propionate