Discovery of DFV890, a Potent Sulfonimidamide-Containing NLRP3 Inflammasome Inhibitor

The discovery of DFV890 ((<i>R</i>)-<b>1</b>), a potent and selective NLRP3 antagonist, is described. Replacement of the sulfonyl urea core from the first-generation NLRP3 antagonist CRID3 with a sulfonimidamide core afforded a novel and potent series of NLRP3 antagonists. The <i>(R)-</i>enantiomers of the sulfonimidamide series were found to be consistently more potent than structurally related sulfonyl ureas. Replacement of the furan unit of CRID3 with a 5-substituted thiazole unit led to DFV890 ((<i>R</i>)-<b>1</b>), which potently inhibited IL-1β production in THP-1 cells and in primary human cells, blocked multiple downstream effectors of NLRP3 activation, and substantially improved PK properties and significantly lowered the predicted human dose compared to that for CRID3. DFV890 ((<i>R</i>)-<b>1</b>) was also effective in an air pouch model of gout.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2025-03-04
DOI
https://doi.org/10.1021/acs.jmedchem.4c02759
Citations
22
Primary Topic
Inflammasome and immune disorders
Type
article
Field-Weighted Citation Impact
17.73
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article

Discovery of DFV890, a Potent Sulfonimidamide-Containing NLRP3 Inflammasome Inhibitor

Ayman El‐Kattan, Anthony W. Opipari, Dong-Ming Shen, Gary D. Glick et al.
22 citations
Journal of Medicinal Chemistry
Inflammasome and immune disorders
17.73
article

Discovery of DFV890, a Potent Sulfonimidamide-Containing NLRP3 Inflammasome Inhibitor

Ayman El‐Kattan, Anthony W. Opipari, Dong-Ming Shen, Gary D. Glick, James Stunden, Carien Dekker, Sarah Bradley, William Roush, Simona Braams, Damien Bertheloot, Alexandra Hinniger, Edward J. Olhava, Jason D. Katz, Dennis Dean, Xiaokang Lu, Ana Kitanovic, Luigi Franchi, H. Martin Seidel, Andrea Stutz, Kate F. Byth, David G. Winkler, Shankar Venkatraman, Shomir Ghosh, Brian Sanchez, Alissa Telling
article en
22 citations

Abstract

The discovery of DFV890 ((<i>R</i>)-<b>1</b>), a potent and selective NLRP3 antagonist, is described. Replacement of the sulfonyl urea core from the first-generation NLRP3 antagonist CRID3 with a sulfonimidamide core afforded a novel and potent series of NLRP3 antagonists. The <i>(R)-</i>enantiomers of the sulfonimidamide series were found to be consistently more potent than structurally related sulfonyl ureas. Replacement of the furan unit of CRID3 with a 5-substituted thiazole unit led to DFV890 ((<i>R</i>)-<b>1</b>), which potently inhibited IL-1β production in THP-1 cells and in primary human cells, blocked multiple downstream effectors of NLRP3 activation, and substantially improved PK properties and significantly lowered the predicted human dose compared to that for CRID3. DFV890 ((<i>R</i>)-<b>1</b>) was also effective in an air pouch model of gout.

Journal of Medicinal ChemistryVol. 68(5)
Novartis (China) (CN), Ifm Therapeutics (United States) (US)
Clean water and sanitation
Openalex Percentile: Top 1%
Inflammasome and immune disorders
17.73
DOISourceOpenAlex
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