Discovery of gamma-lactam hydroxamic acids as selective inhibitors of tumor necrosis factor alpha converting enzyme: design, synthesis, and structure-activity relationships

James J-W Duan; Lihua Chen; Zelda R Wasserman; Zhonghui Lu; Rui-Qin Liu; Maryanne B Covington; Mingxin Qian; Karl D Hardman; Ronald L Magolda; Robert C Newton; David D Christ; Ruth R Wexler; Carl P Decicco

doi:10.1021/jm0255670

Discovery of gamma-lactam hydroxamic acids as selective inhibitors of tumor necrosis factor alpha converting enzyme: design, synthesis, and structure-activity relationships

J Med Chem. 2002 Nov 7;45(23):4954-7. doi: 10.1021/jm0255670.

Authors

James J-W Duan¹, Lihua Chen, Zelda R Wasserman, Zhonghui Lu, Rui-Qin Liu, Maryanne B Covington, Mingxin Qian, Karl D Hardman, Ronald L Magolda, Robert C Newton, David D Christ, Ruth R Wexler, Carl P Decicco

Affiliation

¹ Discovery Chemistry, Bristol-Myers Squibb Company, Experimental Station, Wilmington, Delaware 19880-0500, USA. [email protected]

PMID: 12408705
DOI: 10.1021/jm0255670

Abstract

New gamma-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of TACE was built and examined to identify the S1' site as the key area for TACE selectivity over MMPs. Rational exploration of the P1'-S1' interactions resulted in the discovery of the 3,5-disubstituted benzyl ether as a TACE-selective P1' group. Further optimization led to the discovery of IK682 as a selective and orally bioavailable TACE inhibitor.

MeSH terms

ADAM Proteins
ADAM17 Protein
Administration, Oral
Animals
Biological Availability
Dogs
Hydroxamic Acids / chemical synthesis*
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology
Lactams / chemical synthesis*
Lactams / chemistry
Lactams / pharmacology
Matrix Metalloproteinase 3 / chemistry
Metalloendopeptidases / antagonists & inhibitors*
Models, Molecular
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Swine

Substances

Hydroxamic Acids
IK 682
Lactams
Protease Inhibitors
ADAM Proteins
Metalloendopeptidases
Matrix Metalloproteinase 3
ADAM17 Protein
Adam17 protein, rat