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

Gernot Langer, Nico Bräuer, Daryl Walter, Stuart Flanagan, Olivier Rémi Barbeau, Wei Tsung Yau, James Jenkins, Dennis Wegener, Daren Fearon, Anne-Marie Coelho, Benjamin Bader, Anders Friberg, Hartmut Beck, Vera Pütter, Frank Sacher
Journal of medicinal chemistry · 2026 · vol. 69(11) , pp. 13551–13575 · doi:10.1021/acs.jmedchem.6c00488 · PMID:42153258
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The paper describes the discovery and optimization of BAY-439, a piperidyl urea derivative designed to selectively inhibit human phospholipase A2 group V (hPLA2-G5), a target implicated in inflammatory pain through mechanisms such as neutrophil/macrophage recruitment, arachidonic acid release, and PGE2 production. Using high-throughput and fragment-based screening, the authors optimized physicochemical and pharmacokinetic properties of initial hits to achieve single-digit nanomolar potency, and they provide BAY-439 alongside an inactive negative probe (BAY-163) as freely available tools. A key limitation stated in the abstract is that the work is focused on identification of pharmacological inhibitors rather than demonstrating disease efficacy in endometriosis itself. This paper is centrally about endometriosis—hPLA2-G5 is explicitly discussed as a promising therapeutic target for inflammatory pain in endometriosis, motivating the compound development.

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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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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 PainClick to copy article linkArticle link copied! - Gernot LangerGernot LangerBayer AG, Research & Development, Pharmaceuticals, Müllerstrasse 170, 13342 Berlin, GermanyMore by Gernot Langer - Nico Bräuer - Daryl WalterDaryl WalterEvotec (U.K.) Ltd, 112-114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.More by Daryl Walter - Stuart FlanaganStuart FlanaganEvotec (U.K.) Ltd, 112-114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.More by Stuart Flanagan - Olivier Rémi BarbeauOlivier Rémi BarbeauEvotec (U.K.) Ltd, 112-114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.More by Olivier Rémi Barbeau - Wei Tsung YauWei Tsung YauEvotec (U.K.) Ltd, 112-114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.More by Wei Tsung Yau - James JenkinsJames JenkinsEvotec (U.K.) Ltd, 112-114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.More by James Jenkins - Dennis Wegener - Daren FearonDaren FearonEvotec (U.K.) Ltd, 112-114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.More by Daren Fearon - Anne-Marie Coelho - Benjamin Bader - Anders Friberg - Hartmut BeckHartmut BeckBayer AG, Research & Development, Pharmaceuticals, Aprather Weg 18a, 42113 Wuppertal, GermanyMore by Hartmut Beck - Vera Pütter - Frank Sacher*Frank Sacher*Email: [email protected]. Phone: +493046815933.Bayer AG, Research & Development, Pharmaceuticals, Müllerstrasse 170, 13342 Berlin, GermanyMore by Frank Sacher 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. Cited By This article has not yet been cited by other publications. Article Views Altmetric Citations Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days. Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts. The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

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MeSH descriptors

Inflammation Inflammation Inflammation Inflammation Inflammation Pain Pain Pain Pain Pain Phospholipase A2 Inhibitors Phospholipase A2 Inhibitors Phospholipase A2 Inhibitors Phospholipase A2 Inhibitors Phospholipase A2 Inhibitors Phospholipase A2 Inhibitors Phospholipase A2 Inhibitors Phospholipase A2 Inhibitors Piperidines Piperidines

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