Tandem optimization of target activity and elimination of mutagenic potential in a potent series of N-aryl bicyclic hydantoin-based selective androgen receptor modulators

Lawrence G Hamann; Mark C Manfredi; Chongqing Sun; Stanley R Krystek Jr; Yanting Huang; Yingzhi Bi; David J Augeri; Tammy Wang; Yan Zou; David A Betebenner; Aberra Fura; Ramakrishna Seethala; Rajasree Golla; Joyce E Kuhns; John A Lupisella; Celia J Darienzo; Laura L Custer; Jennifer L Price; James M Johnson; Scott A Biller; Robert Zahler; Jacek Ostrowski

doi:10.1016/j.bmcl.2007.01.076

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. doi: 10.1016/j.bmcl.2007.01.076. Epub 2007 Jan 27.

Affiliation

¹ Bristol-Myers Squibb, Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA. lawrence.hamann@bms.com

PMID: 17292608
DOI: 10.1016/j.bmcl.2007.01.076

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.

MeSH terms

Androgen Antagonists / chemical synthesis*
Androgen Antagonists / chemistry*
Androgen Antagonists / pharmacology
Animals
Chemistry, Pharmaceutical / methods*
Drug Design
Escherichia coli / metabolism
Genes, Reporter
Hydantoins / chemical synthesis*
Hydantoins / chemistry*
Kinetics
Macaca fascicularis
Models, Chemical
Molecular Conformation
Mutagenesis
Mutagens
Receptors, Androgen / metabolism*
Structure-Activity Relationship

Substances

Androgen Antagonists
Hydantoins
Mutagens
Receptors, Androgen