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Pyrazole-Based Transthyretin Kinetic Stabilizers Identified Using a Covalent Fluorescent Probe Assay for Selectivity

Kyung Ah Kim1, Chaeeun Lee1, Nayoung Lim1

  • 1Department of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea.

Journal of Medicinal Chemistry
|December 9, 2025
PubMed
Summary

Researchers developed novel pyrazole-based compounds to stabilize transthyretin (TTR), preventing amyloidosis. These stabilizers show promise for treating hereditary and wild-type TTR amyloidosis, with some matching existing therapies.

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Area of Science:

  • Medicinal Chemistry
  • Biochemistry
  • Drug Discovery

Background:

  • Transthyretin (TTR) amyloidosis is caused by misfolded TTR protein forming amyloid fibrils.
  • These fibrils deposit in tissues, leading to progressive organ damage.

Purpose of the Study:

  • To design and synthesize novel pyrazole-based kinetic stabilizers for TTR.
  • To evaluate the efficacy and selectivity of these stabilizers in inhibiting TTR aggregation.

Main Methods:

  • Structure-activity relationship (SAR) studies of pyrazole derivatives.
  • Development of a covalent fluorescent probe for selectivity assays.
  • Evaluation of stabilizer efficacy using fluorescence probe exclusion and native PAGE.
  • X-ray crystallography to elucidate binding interactions.
  • Pharmacokinetic studies to assess drug-like properties.

Main Results:

  • Pyrazole derivatives with hydrophobic trans-alkene linkers and specific substituents showed potent TTR stabilization.
  • 3,5-dichloropyrazole derivatives demonstrated efficacy comparable to tafamidis and acoramidis.
  • X-ray crystallography confirmed specific hydrogen bonding and electrostatic interactions.
  • Compounds 16 and 17 exhibited favorable pharmacokinetic profiles, including good bioavailability and metabolic stability.

Conclusions:

  • Novel pyrazole-based compounds effectively stabilize TTR and inhibit amyloid formation.
  • These compounds represent promising preclinical candidates for treating TTR amyloidosis.
  • The developed covalent probe is valuable for assessing stabilizer selectivity in complex biological matrices.