Identification of the Piperidyl Urea Derivative BAY-439 as a Potent and Selective Inhibitor of Human Phospholipase A2 Group V (hPLA2-G5) for the Treatment of Inflammatory Pain

Human Phospholipase A₂ Group V (hPLA₂-G5) is elevated in inflammatory conditions and promotes neutrophil and macrophage recruitment. Its enzymatic activity activates lipid receptors and cytosolic Phospholipase A₂ (cPLA₂), leading to arachidonic acid release and PGE₂ production─key mediators of chronic inflammation. Thus, hPLA₂-G5 represents a promising therapeutic target for diseases with inflammatory pain, such as in endometriosis─a highly debilitating disease characterized by the ectopic growth of endometriotic cells in the abdominal cavity. High-throughput and fragment-based screening identified structurally related small molecule hits. Optimization of the physicochemical and pharmacokinetic properties of the HTS hit led to the identification of BAY-439, a potent and selective hPLA₂-G5 inhibitor with single-digit nanomolar activity. Accepted as a donated chemical probe by the Structural Genomics Consortium, both BAY-439 and the inactive negative probe BAY-163 are freely available as valuable pharmacological tools to investigate the role of hPLA₂-G5 both under physiological and pathological conditions.