37EF

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

This is a non-PDB format compatible entry.

Summary for 37EF

• Entry DOI: 10.2210/pdb37ef/pdb
• Related: 37DK
• Descriptor: Transthyretin, 3-[1-(3,5-dimethyl-1H-pyrazol-4-yl)piperidin-4-yl]-2,4-dimethoxypyridine (3 entities in total)
• Functional Keywords: transthyretin, heterocyclic, stabilizer, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 28187.52

Authors

Liu, S.,Liu, S. (deposition date: 2026-07-16, release date: 2026-10-07, Last modification date: 2026-11-04)

Primary citation

Wang, T.,Thuma, B.A.,Wisniewska, H.M.,Lee Johnson, Z.,Tu, M.,Byrnes, L.J.,Cabral, S.,Canterbury, D.P.,Clemens, J.,Coffey, S.B.,Dow, R.,Dowling, M.S.,Fensome, A.,Fleming, J.,Futatsugi, K.,Kalgutkar, A.S.,Korczynska, M.,Kung, D.W.,Lapham, K.,Lavergne, S.Y.,Limberakis, C.,Liu, S.,Londregan, A.T.,Loria, P.M.,Mascitti, V.,Moody, A.T.,Novak, J.J.,Piotrowski, D.W.,Sharma, R.,Shavnya, A.,Stock, I.A.,Tess, D.A.,Tsai, A.S.,Wei, L.,Wenzel, Z.,Wu, H.
Discovery of Neutral and Cerebrospinal Fluid Penetrant Transthyretin (TTR) Stabilizers with Heterocyclic Linkers.
J.Med.Chem., 69:22942-22953, 2026

PubMed 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.

PubMed: 42917948
DOI: 10.1021/acs.jmedchem.6c02318

Experimental method

X-RAY DIFFRACTION (1.278 Å)