DOI: 10.1021/acs.jmedchem.6c02318 ISSN: 0022-2623
Discovery of Neutral and Cerebrospinal Fluid Penetrant Transthyretin (TTR) Stabilizers with Heterocyclic Linkers
Tao Wang, Benjamin A. Thuma, Hanna M. Wisniewska, Zachary Lee Johnson, Meihua Tu, Laura J. Byrnes, Shawn Cabral, Daniel P. Canterbury, Jennifer Clemens, Steven B. Coffey, Robert Dow, Matthew S. Dowling, Andrew Fensome, James Fleming, Kentaro Futatsugi, Amit S. Kalgutkar, Magdalena Korczynska, Daniel W. Kung, Kimberly Lapham, Sophie Y. Lavergne, Chris Limberakis, Shenping Liu, Allyn T. Londregan, Paula M. Loria, Vincent Mascitti, Amy Thurber Moody, Jonathan J. Novak, David W. Piotrowski, Raman Sharma, Andre Shavnya, Ingrid A. Stock, David A. Tess, Andy S. Tsai, Liuqing Wei, Zane Wenzel, Huixian WuAbstract
Human transthyretin (TTR) is associated with ATTR amyloidosis. Despite having approved agents against TTR, there is still an unmet medical need to develop novel agents, especially those that could have therapeutic effects in cerebrospinal fluid (CSF). Structure-based drug design (SBDD) in the thyroxine binding pocket of TTR identified a neutral hit. Further optimization led to compound 9, a neutral TTR tetramer stabilizer with single-digit nM SPR Kd potency and with improved ADME profile that could enable it to penetrate to CSF.