Tandem optimization of target activity and elimination of mutagenic potential in a potent series of N-aryl bicyclic hydantoin-based selective androgen receptor modulators.
Article Details
- CitationCopy to clipboard
Hamann LG, Manfredi MC, Sun C, Krystek SR Jr, Huang Y, Bi Y, Augeri DJ, Wang T, Zou Y, Betebenner DA, Fura A, Seethala R, Golla R, Kuhns JE, Lupisella JA, Darienzo CJ, Custer LL, Price JL, Johnson JM, Biller SA, Zahler R, Ostrowski J
Tandem optimization of target activity and elimination of mutagenic potential in a potent series of N-aryl bicyclic hydantoin-based selective androgen receptor modulators.
Bioorg Med Chem Lett. 2007 Apr 1;17(7):1860-4. Epub 2007 Jan 27.
- PubMed ID
- 17292608 [ View in PubMed]
- Abstract
Pharmacokinetic studies in cynomolgus monkeys with a novel prototype selective androgen receptor modulator revealed trace amounts of an aniline fragment released through hydrolytic metabolism. This aniline fragment was determined to be mutagenic in an Ames assay. Subsequent concurrent optimization for target activity and avoidance of mutagenicity led to the identification of a pharmacologically superior clinical candidate without mutagenic potential.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) 4-[(7R,7AS)-7-HYDROXY-1,3-DIOXOTETRAHYDRO-1H-PYRROLO[1,2-C]IMIDAZOL-2(3H)-YL]-1-NAPHTHONITRILE Androgen receptor EC 50 (nM) 2.3 N/A N/A Details 4-[(7R,7AS)-7-HYDROXY-1,3-DIOXOTETRAHYDRO-1H-PYRROLO[1,2-C]IMIDAZOL-2(3H)-YL]-1-NAPHTHONITRILE Androgen receptor Ki (nM) 3.2 N/A N/A Details BMS-564929 Androgen receptor EC 50 (nM) 0.7 N/A N/A Details BMS-564929 Androgen receptor Ki (nM) 2.1 N/A N/A Details