Discovery of beta-benzamido hydroxamic acids as potent, selective, and orally bioavailable TACE inhibitors

James J-W Duan; Lihua Chen; Zhonghui Lu; Chu-Biao Xue; Rui-Qin Liu; Maryanne B Covington; Mingxin Qian; Zelda R Wasserman; Krishna Vaddi; David D Christ; James M Trzaskos; Robert C Newton; Carl P Decicco

doi:10.1016/j.bmcl.2007.10.093

Discovery of beta-benzamido hydroxamic acids as potent, selective, and orally bioavailable TACE inhibitors

Bioorg Med Chem Lett. 2008 Jan 1;18(1):241-6. doi: 10.1016/j.bmcl.2007.10.093. Epub 2007 Oct 30.

Authors

James J-W Duan¹, Lihua Chen, Zhonghui Lu, Chu-Biao Xue, Rui-Qin Liu, Maryanne B Covington, Mingxin Qian, Zelda R Wasserman, Krishna Vaddi, David D Christ, James M Trzaskos, Robert C Newton, Carl P Decicco

Affiliation

¹ Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. james.duan@bms.com

PMID: 18032037
DOI: 10.1016/j.bmcl.2007.10.093

Abstract

Beta-benzamido hydroxamic acids were discovered as potent TACE inhibitors. A computer model was constructed to help understanding the binding activities and guiding SAR study. SAR optimization led to the discovery of compound 30 which met all in vitro and in vivo criteria for the program and was selected for further evaluation.

MeSH terms

ADAM Proteins / antagonists & inhibitors*
ADAM Proteins / chemistry
ADAM Proteins / metabolism
ADAM17 Protein
Administration, Oral
Animals
Benzamides / chemistry
Benzamides / pharmacokinetics
Benzamides / pharmacology
Binding Sites
Biological Availability
Dogs
Hydroxamic Acids / chemistry*
Hydroxamic Acids / pharmacokinetics
Hydroxamic Acids / pharmacology*
Models, Molecular
Protease Inhibitors / chemistry*
Protease Inhibitors / pharmacokinetics
Protease Inhibitors / pharmacology*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Swine

Substances

Benzamides
Hydroxamic Acids
Protease Inhibitors
ADAM Proteins
ADAM17 Protein
Adam17 protein, rat