title: Tandem optimization of target activity and elimination of mutagenic potential in a potent series of N-aryl bicyclic hydantoin-based selective androgen receptor modulators.
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.
authors.affiliation: Bristol-Myers Squibb, Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA. lawrence.hamann@bms.com
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Hamann
authors.forename: Mark C
authors.initials: MC
authors.lastname: Manfredi
authors.forename: Chongqing
authors.initials: C
authors.lastname: Sun
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Krystek
authors.forename: Yanting
authors.initials: Y
authors.lastname: Huang
authors.forename: Yingzhi
authors.initials: Y
authors.lastname: Bi
authors.forename: David J
authors.initials: DJ
authors.lastname: Augeri
authors.forename: Tammy
authors.initials: T
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zou
authors.forename: David A
authors.initials: DA
authors.lastname: Betebenner
authors.forename: Aberra
authors.initials: A
authors.lastname: Fura
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Seethala
authors.forename: Rajasree
authors.initials: R
authors.lastname: Golla
authors.forename: Joyce E
authors.initials: JE
authors.lastname: Kuhns
authors.forename: John A
authors.initials: JA
authors.lastname: Lupisella
authors.forename: Celia J
authors.initials: CJ
authors.lastname: Darienzo
authors.forename: Laura L
authors.initials: LL
authors.lastname: Custer
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Price
authors.forename: James M
authors.initials: JM
authors.lastname: Johnson
authors.forename: Scott A
authors.initials: SA
authors.lastname: Biller
authors.forename: Robert
authors.initials: R
authors.lastname: Zahler
authors.forename: Jacek
authors.initials: J
authors.lastname: Ostrowski
mesh_terms: D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004926:Escherichia coli / Q000378:metabolism; D017930:Genes, Reporter; D006827:Hydantoins / Q000138:chemical synthesis* / Q000737:chemistry*; D007700:Kinetics; D008252:Macaca fascicularis; D008956:Models, Chemical; D008968:Molecular Conformation; D016296:Mutagenesis; D009153:Mutagens; D011944:Receptors, Androgen / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000726:Androgen Antagonists; D006827:Hydantoins; D009153:Mutagens; D011944:Receptors, Androgen