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Advancing NLRP3 Inhibition: Novel Chemotypes Emerge in Clinical Trials

• AstraZeneca and Mitsubishi Tanabe are advancing AZD4144, a novel NLRP3 inhibitor, through Phase I trials in healthy volunteers, exploring new chemotypes. • The discovery of AZD4144 involved overcoming challenges such as phospholipidosis, genotoxicity, and hERG inhibition, as presented at the EFMC-ISMC 2024 Meeting. • Recent efforts have focused on developing NLRP3 inflammasome inhibitors, including Nodthera’s ND-0796, showcasing a growing interest in this therapeutic target.

The pursuit of effective NLRP3 inflammasome inhibitors is gaining momentum, with several compounds entering clinical development. AstraZeneca and Mitsubishi Tanabe are currently conducting Phase I trials of AZD4144 in healthy volunteers, representing a novel chemotype in this therapeutic area. This push for new chemotypes comes amid a surge of (pre)clinical compounds inhibiting the NLRP3 inflammasome, often featuring a hexahydroindacene ring system, including Nodthera’s ND-0796.
The discovery of AZD4144 involved significant efforts to overcome several pharmacological challenges. As presented by Anders Johansson at the EFMC-ISMC 2024 Meeting in Rome, the development team addressed issues related to phospholipidosis (PLD), genotoxicity, and hERG inhibition within a non-classical pharmacophore series. These efforts highlight the complexities involved in developing safe and effective NLRP3 inhibitors.
The NLRP3 inflammasome is a key component of the innate immune system, implicated in a variety of inflammatory diseases. Inhibition of this pathway represents a promising therapeutic strategy for conditions with significant unmet medical needs. The emergence of multiple compounds targeting NLRP3, each with unique structural and pharmacological properties, underscores the growing interest and investment in this area of research.
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Reference News

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A Potential First-in-Class Selective CK1α Molecular Glue Degrader
drughunter.com · Oct 25, 2024

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