Discovery of AZD4144, a Selective and Potent NLRP3 Inhibitor for the Treatment of Inflammatory Diseases

Inflammatory disease is a major burden on health care, and new treatments are needed to manage exaggerated inflammatory responses. The NLRP3 inflammasome is a key player in inflammation, the activation of which is believed to be associated with an increased cardiovascular and renal risk and play a major role in several common noncommunicable diseases. The emergence of evidence that small molecules can work as NLRP3 inhibitors has initiated a surge of drug discovery activities within the field. In this paper, we describe the discovery of the clinical candidate AZD4144. The compound inhibits NLRP3 selectively with high potency, has beneficial pharmacokinetic properties, and shows a favorable off-target pharmacology profile. We also show that AZD4144 binds directly to NLRP3 and competes with MCC950 for binding to the protein, indicating that the likely mode of inhibition of AZD4144 is to stabilize the inactive form of NLRP3.