The NLRP3 inflammasome is a component of the innate immune system involved in the production of pro-inflammatory cytokines. Aberrant activation by a wide range of exogenous and endogenous signals can lead to chronic, low-grade inflammation. Inhibition of the NLRP3 inflammasome with small molecules represents a potential treatment for several debilitating diseases with a large unmet medical need, including Alzheimer’s disease, Parkinson’s disease, arthritis and cancer. Despite a great deal of interest, there are currently no specific NLRP3 inflammasome inhibitors on the market. In this presentation I will describe the medicinal chemistry approach leading to the discovery of a new class of small molecule NLRP3 inflammasome inhibitors. The starting point for this program was the safe, well-tolerated and selective NLRP3 inflammasome inhibitor CP-456,773 (aka MCC950). We employed a de novo approach to systematically fragment this compound and assessed the SAR of the truncated molecules. This led to the discovery of a novel series of ester-based molecules with different characteristics to the state of the art. The best compounds from this series are up to 20-fold more potent than CP-456,773 in the human whole blood assay, the most relevant for predicting human efficacy. These esters are highly differentiated from other literature NLRP3 inhibitors and have the potential for further optimisation.

Novel ester-based NLRP3 inflammasome inhibitors

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.