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

  • J Med Chem. 2026 Jun 11;69(11):13551-13575. doi: 10.1021/acs.jmedchem.6c00488.
Gernot Langer  1 ,  Nico Bräuer  2 ,  Daryl Walter  3 ,  Stuart Flanagan  3 ,  Olivier Rémi Barbeau  3 ,  Wei Tsung Yau  3 ,  James Jenkins  3 ,  Dennis Wegener  4 ,  Daren Fearon  3 ,  Anne-Marie Coelho  4 ,  Benjamin Bader  2 ,  Anders Friberg  2 ,  Hartmut Beck  5 ,  Vera Pütter  2 ,  Frank Sacher  1
Affiliations
  • 1. Bayer AG, Research & Development, Pharmaceuticals, Müllerstrasse 170, 13342 Berlin, Germany.
  • 2. Nuvisan ICB GmbH, Müllerstrasse 178, 13353 Berlin, Germany.
  • 3. Evotec (U.K.) Ltd, 112-114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • 4. Evotec SE, Essener Bogen 7, 22419 Hamburg, Germany.
  • 5. Bayer AG, Research & Development, Pharmaceuticals, Aprather Weg 18a, 42113 Wuppertal, Germany.
PMID: 42153258 DOI: 10.1021/acs.jmedchem.6c00488
Abstract

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.

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