Acetylenic TACE inhibitors. Part 1. SAR of the acyclic sulfonamide hydroxamates

The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors, all bearing a butynyloxy P1′ group, was explored. In particular, compound 5j has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and MMP-9, and oral activity in an in vivo model o...

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Published in:	Bioorganic & medicinal chemistry letters Vol. 13; no. 16; pp. 2799 - 2803
Main Authors:	Levin, J.I., Chen, J.M., Cheung, K., Cole, D., Crago, C., Santos, E.Delos, Du, X., Khafizova, G., MacEwan, G., Niu, C., Salaski, E.J., Zask, A., Cummons, T., Sung, A., Xu, J., Zhang, Y., Xu, W., Ayral-Kaloustian, S., Jin, G., Cowling, R., Barone, D., Mohler, K.M., Black, R.A., Skotnicki, J.S.
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 18-08-2003 Elsevier
Subjects:	Acetylene - chemistry ADAM Proteins ADAM17 Protein Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Crystallography, X-Ray Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Hydroxamic Acids - chemistry Medical sciences Metalloendopeptidases - antagonists & inhibitors Molecular Structure ortho-Aminobenzoates - chemistry ortho-Aminobenzoates - pharmacology Pharmacology. Drug treatments Structure-Activity Relationship Sulfonamides - chemistry Animal model Acetylenic compound Diseases of the osteoarticular system Metalloendopeptidases Inflammatory joint disease Arthritis Selectivity Structure activity relation Secondary alcohol Chemical synthesis Tumor necrosis factor α Immunopathology Sulfonamide Enzyme Rodentia Antiinflammatory agent Hydroxamic acid Enzyme inhibitor In vitro Peptidases In vivo α-Aminoacid Vertebrata Experimental disease Mammalia Mouse Collagen Hydrolases
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Summary:	The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors, all bearing a butynyloxy P1′ group, was explored. In particular, compound 5j has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and MMP-9, and oral activity in an in vivo model of TNF-α production and a collagen-induced arthritis model. Compound 5j, a potent and selective inhibitor of TACE, in vitro and in vivo, has been identified.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/S0960-894X(03)00514-6