1. Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates
- Author
-
J.S. Skotnicki, James M. Chen, Jun Xu, Dauphine Barone, L.M. Laakso, J. Schmid, Weixin Xu, G. Jin, Terri Cummons, Jeremy I. Levin, and Mila T. Du
- Subjects
Lipopolysaccharides ,Propanols ,Stereochemistry ,Morpholines ,Clinical Biochemistry ,Administration, Oral ,Pharmaceutical Science ,Ether ,ADAM17 Protein ,Matrix Metalloproteinase Inhibitors ,Crystallography, X-Ray ,Hydroxamic Acids ,Biochemistry ,Chemical synthesis ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dogs ,In vivo ,Matrix Metalloproteinase 13 ,Drug Discovery ,Animals ,Humans ,Enzyme Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,Sulfonamides ,Hydroxamic acid ,Molecular Structure ,biology ,Acetylene ,Tumor Necrosis Factor-alpha ,Arthritis ,Organic Chemistry ,Haplorhini ,Rats ,Sulfonamide ,ADAM Proteins ,Disease Models, Animal ,Enzyme ,Thiomorpholine ,chemistry ,Enzyme inhibitor ,Alkynes ,biology.protein ,Molecular Medicine ,Collagen ,Caco-2 Cells - 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-α production and a collagen-induced arthritis model, was selected as a clinical candidate for the treatment of RA.
- Published
- 2006