Discovery of Neutral and Cerebrospinal Fluid Penetrant Transthyretin (TTR) Stabilizers with Heterocyclic Linkers

  • J Med Chem. 2026 Oct 8;69(19):22942-22953. doi: 10.1021/acs.jmedchem.6c02318.
Tao Wang  1 ,  Benjamin A Thuma  2 ,  Hanna M Wisniewska  3 ,  Zachary Lee Johnson  2 ,  Meihua Tu  1 ,  Laura J Byrnes  2 ,  Shawn Cabral  2 ,  Daniel P Canterbury  2 ,  Jennifer Clemens  2 ,  Steven B Coffey  2 ,  Robert Dow  1 ,  Matthew S Dowling  2 ,  Andrew Fensome  1 ,  James Fleming  1 ,  Kentaro Futatsugi  1 ,  Amit S Kalgutkar  1 ,  Magdalena Korczynska  1 ,  Daniel W Kung  2 ,  Kimberly Lapham  2 ,  Sophie Y Lavergne  2 ,  Chris Limberakis  2 ,  Shenping Liu  2 ,  Allyn T Londregan  1 ,  Paula M Loria  2 ,  Vincent Mascitti  1 ,  Amy Thurber Moody  1 ,  Jonathan J Novak  2 ,  David W Piotrowski  2 ,  Raman Sharma  2 ,  Andre Shavnya  2 ,  Ingrid A Stock  2 ,  David A Tess  1 ,  Andy S Tsai  2 ,  Liuqing Wei  2 ,  Zane Wenzel  2 ,  Huixian Wu  2
Affiliations
  • 1. Pfizer Research & Development , 1 Portland Street, Cambridge, Massachusetts02139, United States.
  • 2. Pfizer Research & Development, 445 Eastern Point Road, Groton, Connecticut06340, United States.
  • 3. Pfizer Research & Development, 11202 El Camino Real, San Diego, California92130, United States.
PMID: 42917948 DOI: 10.1021/acs.jmedchem.6c02318
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.

Keywords
ATTR amyloidosis; CSF penetrant; TTR; transthyretin.
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