Structure and activity relationships of tartrate-based TACE inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2010-08, Vol.20 (16), p.4812-4815
• Main Authors: Li, Dansu, Popovici-Muller, Janeta, Belanger, David B., Caldwell, John, Dai, Chaoyang, David, Maria, Girijavallabhan, Vinay M., Lavey, Brian J., Lee, Joe F., Liu, Zhidan, Mazzola, Rob, Rizvi, Razia, Rosner, Kristin E., Shankar, Bandarpalle, Spitler, Jim, Ting, Pauline C., Vaccaro, Henry, Yu, Wensheng, Zhou, Guowei, Zhu, Zhaoning, Niu, Xiaoda, Sun, Jing, Guo, Zhuyan, Orth, Peter, Chen, Shiying, Kozlowski, Joseph A., Lundell, Daniel J., Madison, Vincent, McKittrick, Brian, Piwinski, John J., Shih, Neng-Yang, Shipps, Gerald W., Siddiqui, M. Arshad, Strickland, Corey O.
• Format: Article
• Language: English
• Subjects: ADAM Proteins - antagonists & inhibitors; ADAM Proteins - metabolism; ADAM17 Protein; Animals; Binding Sites; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Computer Simulation; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacokinetics; Rats; Rheumatoid arthritis; Structure-Activity Relationship; TACE inhibitor; Tartrates; Tartrates - chemical synthesis; Tartrates - chemistry; Tartrates - pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.06.104

The syntheses and structure–activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.