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.
Schlienger
Nathalie
N
ACADIA Pharmaceuticals AB, Medeon Science Park, S-205 12 Malmo, Sweden.
Lund
Birgitte W
BW
Pawlas
Jan
J
Badalassi
Fabrizio
F
Bertozzi
Fabio
F
Lewinsky
Rasmus
R
Fejzic
Alma
A
Thygesen
Mikkel B
MB
Tabatabaei
Ali
A
Bradley
Stefania Risso
SR
Gardell
Luis R
LR
Piu
Fabrice
F
Olsson
Roger
R
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