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

被引：27

作者：

Hamann, Lawrence G. ^{[1
]}

Manfredi, Mark C. ^{[1
]}

Sun, Chongqing ^{[1
]}

Krystek, Stanley R., Jr. ^{[1
]}

Huang, Yanting ^{[1
]}

Bi, Yingzhi ^{[1
]}

Augeri, David J. ^{[1
]}

Wang, Tammy ^{[1
]}

Zou, Yan ^{[1
]}

Betebenner, David. A. ^{[1
]}

Fura, Aberra ^{[1
]}

Seethala, Ramakrishna ^{[1
]}

Golla, Rajasree ^{[1
]}

Kuhns, Joyce E. ^{[1
]}

Lupisella, John A. ^{[1
]}

Darienzo, Celia J. ^{[1
]}

Custer, Laura L. ^{[1
]}

Price, Jennifer L. ^{[1
]}

Johnson, James M. ^{[1
]}

Biller, Scott A. ^{[1
]}

Zahler, Robert ^{[1
]}

Ostrowski, Jacek ^{[1
]}

机构：

[1] Bristol Myers Squibb, Pharmaceut Res Inst, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 07期

关键词：

SARM; androgen; receptor; mutagenicity; aniline;

D O I：

10.1016/j.bmcl.2007.01.076

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Pharmacokinctic 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. (c) 2007 Elsevier Ltd. All rights reserved.

引用

页码：1860 / 1864

页数：5

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