Discovery of Neutral and Cerebrospinal Fluid Penetrant Transthyretin (TTR) Stabilizers with Heterocyclic Linkers
Abstract
Abstract 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.
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Authors: Tao Wang, Benjamin A. Thuma, Hanna M. Wisniewska, Zachary Lee Johnson, 涂梅花, Laura J. Byrnes, Shawn Cabral, Daniel P. Canterbury, Jennifer Clemens, Steven B. Coffey, Robert Dow, Matthew Dowling, Andrew Fensome, James Fleming, Kentaro Futatsugi, Amit S.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 T. Moody, Jonathan J. Novak, David W. Piotrowski, R Sharma, Andre Shavnya, Ingrid A. Stock, David A. Tess, Andy S. Tsai, Liuqing Wei, Zane Wenzel, Huixian Wu
Institutions: Pfizer (United States)