1.
Bioorg Med Chem Lett
; 16(6): 1605-9, 2006 Mar 15.
Article
in English
| MEDLINE
| ID: mdl-16426848
ABSTRACT
A series of thiomorpholine sulfonamide hydroxamate TACE inhibitors, all bearing propargylic ether P1' groups, was explored. In particular, compound 5h has excellent in vitro potency against isolated TACE enzyme and in cells, oral activity in a model of TNF-alpha production and a collagen-induced arthritis model, was selected as a clinical candidate for the treatment of RA.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Acetylene/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , ADAM17 Protein , Administration, Oral , Alkynes/chemistry , Animals , Arthritis/drug therapy , Caco-2 Cells , Collagen/toxicity , Crystallography, X-Ray , Disease Models, Animal , Dogs , Haplorhini , Humans , Hydroxamic Acids/chemistry , Lipopolysaccharides/pharmacology , Matrix Metalloproteinase 13 , Matrix Metalloproteinase Inhibitors , Mice , Molecular Structure , Morpholines/chemistry , Propanols/chemistry , Rats , Structure-Activity Relationship , Sulfonamides/chemistry , Tumor Necrosis Factor-alpha/metabolism
2.
Bioorg Med Chem Lett
; 15(19): 4345-9, 2005 Oct 01.
Article
in English
| MEDLINE
| ID: mdl-16084720
ABSTRACT
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing a butynyloxy P1' group was explored. In particular, compound 5k has excellent in vitro potency against TACE enzyme and in cells, and oral activity in an in vivo model of TNF-alpha production and a collagen-induced arthritis model.
