1. Tandem optimization of target activity and elimination of mutagenic potential in a potent series of N-aryl bicyclic hydantoin-based selective androgen receptor modulators
- Author
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James M. Johnson, David A. Betebenner, Chongqing Sun, Yan Zou, Mark C. Manfredi, Yanting Huang, Tammy C. Wang, Scott A. Biller, Laura Custer, Robert Zahler, Jacek Ostrowski, Jennifer Price, Celia D’Arienzo, Lawrence G. Hamann, Stanley R. Krystek, John A. Lupisella, Rajasree Golla, Ramakrishna Seethala, Joyce E. Kuhns, David J. Augeri, Yingzhi Bi, and Aberra Fura
- Subjects
endocrine system ,Stereochemistry ,Chemistry, Pharmaceutical ,Clinical Biochemistry ,Molecular Conformation ,Pharmaceutical Science ,Hydantoin ,Mutagen ,medicine.disease_cause ,Biochemistry ,Ames test ,chemistry.chemical_compound ,Structure-Activity Relationship ,Genes, Reporter ,Drug Discovery ,medicine ,Escherichia coli ,Animals ,Molecular Biology ,chemistry.chemical_classification ,Bicyclic molecule ,Hydantoins ,fungi ,Organic Chemistry ,food and beverages ,Aromatic amine ,Biological activity ,Androgen Antagonists ,Androgen receptor ,Kinetics ,Macaca fascicularis ,Selective androgen receptor modulator ,chemistry ,Models, Chemical ,Mutagenesis ,Receptors, Androgen ,Drug Design ,Molecular Medicine ,Mutagens - 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.
- Published
- 2006