Tandem optimization of target activity and elimination of mutagenic potential in a potent series of N-aryl bicyclic hydantoin-based selective androgen receptor modulators.
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.
Hamann
Lawrence G
LG
Bristol-Myers Squibb, Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA. lawrence.hamann@bms.com
Manfredi
Mark C
MC
Sun
Chongqing
C
Krystek
Stanley R
SR
Huang
Yanting
Y
Bi
Yingzhi
Y
Augeri
David J
DJ
Wang
Tammy
T
Zou
Yan
Y
Betebenner
David A
DA
Fura
Aberra
A
Seethala
Ramakrishna
R
Golla
Rajasree
R
Kuhns
Joyce E
JE
Lupisella
John A
JA
Darienzo
Celia J
CJ
Custer
Laura L
LL
Price
Jennifer L
JL
Johnson
James M
JM
Biller
Scott A
SA
Zahler
Robert
R
Ostrowski
Jacek
J
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
D000726:Androgen Antagonists; D006827:Hydantoins; D009153:Mutagens; D011944:Receptors, Androgen