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

• Published in: Bioorganic & medicinal chemistry letters 2003-08, Vol.13 (16), p.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: Article
• Language: English
• 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
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00514-6

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.