2-(2-Aminothiazol-4-yl)pyrrolidine-based tartrate diamides as potent, selective and orally bioavailable TACE inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2011-05, Vol.21 (10), p.3172-3176
• Main Authors: Dai, Chaoyang, Li, Dansu, Popovici-Muller, Janeta, Zhao, Lianyun, Girijavallabhan, Vinay M., Rosner, Kristin E., Lavey, Brian J., Rizvi, Razia, Shankar, Bandarpalle B., Wong, Michael K.C., Guo, Zhuyan, Orth, Peter, Strickland, Corey O., Sun, Jing, Niu, Xiaoda, Chen, Shiying, Kozlowski, Joseph A., Lundell, Daniel J., Piwinski, John J., Shih, Neng-Yang, Siddiqui, M. Arshad
• Format: Article
• Language: English
• Subjects: ADAM Proteins - antagonists & inhibitors; ADAM17 Protein; Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; bioavailability; Biological and medical sciences; Biological Availability; Bones, joints and connective tissue. Antiinflammatory agents; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; pyrrolidines; Pyrrolidines - chemistry; Rats; TACE tartrate; Tartrates - chemistry; TNF-α converting enzyme; tumor necrosis factor-alpha; Zinc binding group ( R)-2-(2- N-alkylaminothiazol-4-yl)pyrrolidines
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.01.002

TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating ( R)-2-(2- N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.