Design and synthesis of novel potential NLRP3 inflammasome inhibitors

Abstract

The NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome is a cytosolic multiprotein complex of cells of the innate immune system and mediates the inflammatory response versus a plethora of several stimuli, deriving from pathogens or molecular damages. An overactivation of NLRP3 has been associated with a state of chronic inflammation and has been found in a number of age-related pathological conditions, such as neurodegenerative, cardiovascular, autoimmune, and metabolic diseases. Thus, NLRP3 is a validated target and is appealing for the discovery of new anti-inflammatory drugs. To date, MCC950 is the best lead candidate (IC50 of 8 nM) but failed the clinical trials due to its hepatic and renal toxicity. This inhibitor seems to bind the target in a non-covalent and non-competitive manner at a region proximal to the Walker B, within the NACHT domain. In light of this evidence (pdb 7ALV), we focussed on the design and synthesis of new chemotypes, maintaining the electronic properties of the lead compound, in order to identify novel potential inhibitors of the NLRP3 machinery. In detail, five chemotypes were designed, and for each class of structures, a feasible, cheap, and no-time-consuming synthetic route was developed.

Impact:

In a highly competitive context, this project aims at discovering new drugs capable of treating chronic inflammation associated with age-related diseases. Currently, no drugs of small molecule nature targeting NLRP3 are available on the market, and only monoclonal antibodies (Anakinra, Canakinumab, Rilonacept) are used for the therapeutic treatment. However, several drawbacks, such as high costs, poor patient compliance, very short plasma half-life (a daily injection is required), the increased risk of contracting infections due to immune system suppression, and poor blood-brain penetration are associated with these biologic drugs. The discovery of small molecule drugs selectively targeting NLRP3 is the goal of several pharmaceutical companies and undoubtedly represents a breakthrough in overcoming the aforementioned limitations, and in improving the quality of life of patients suffering from chronic inflammation. A strength of the project is the presence within the Ri.MED Foundation of a Drug Discovery area that brings together very different expertise and joint skills necessary to face the early discovery phase, helping in the identification of new hits, with the structural optimization of the most promising ones, up to the identification of a lead to be taken further onto the preclinical studies.

Pipeline