{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T13:23:19Z","timestamp":1787404999366,"version":"build-2736575974"},"reference-count":42,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["PR1405\/8-1"],"award-info":[{"award-number":["PR1405\/8-1"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"German Research Council","doi-asserted-by":"publisher","award":["PR1405\/8-1"],"award-info":[{"award-number":["PR1405\/8-1"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Targeting the N-terminal phosphatase domain of soluble epoxide hydrolase (sEH) could potentially represent a pharmacological strategy for treatment of cardiometabolic diseases. However, development of chemical tools to investigate the therapeutic potential of sEH phosphatase (sEH-P) inhibition has proven challenging due to varying activities between different species isoforms and lack of selectivity toward the C-terminal hydrolase domain, which exhibits the epoxide hydrolase activity (sEH-H). Herein, we describe the fragment-based discovery of FZ581 (49), an sEH-P inhibitor against human, rat, and mouse isoforms. In vivo studies with this compound in mice and rats demonstrated a significant increase of main sEH-P substrate levels without affecting plasma levels of sEH-H substrates. Altogether, we provide a pan-species sEH-P inhibitor to study the pharmacotherapeutic potential of sEH-P inhibition.<\/jats:p>","DOI":"10.1021\/acschembio.6c00502","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:14:15Z","timestamp":1785849255000},"page":"2053-2067","source":"Crossref","is-referenced-by-count":0,"title":["Fragment-Based\nDiscovery of Fenamic Acids as Pan-Species\nInhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain"],"prefix":"10.1021","volume":"21","author":[{"given":"W. Felix","family":"Zhu","sequence":"first","affiliation":[{"name":"Goethe University , , ,","place":["Frankfurt am Main, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Feugray","sequence":"additional","affiliation":[{"name":"Univ Rouen Normandie , , ,","place":["Rouen, France, F-76000"]},{"name":"CHU Rouen , , ,","place":["Rouen, France, F-76000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Brunst","sequence":"additional","affiliation":[{"name":"Goethe University , , ,","place":["Frankfurt am Main, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hind","family":"Messaoudi","sequence":"additional","affiliation":[{"name":"Univ Rouen Normandie , , ,","place":["Rouen, France, F-76000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Yang","sequence":"additional","affiliation":[{"name":"University of Science and Technology of China , , ,","place":["Hefei, China, 230027"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4589-1620","authenticated-orcid":true,"given":"Noemi","family":"Martinez-Conde","sequence":"additional","affiliation":[{"name":"Goethe University , , ,","place":["Frankfurt am Main, Germany, 60438"]},{"name":"University of Barcelona (UB) , , ,","place":["Barcelona, Spain, E-08028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Kra\u0308mer","sequence":"additional","affiliation":[{"name":"Goethe University , , ,","place":["Frankfurt am Main, Germany, 60438"]},{"name":"Buchmann Institute for Molecular Life Sciences (BMLS) , , ,","place":["Frankfurt am Main, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilia","family":"Weizel","sequence":"additional","affiliation":[{"name":"Goethe University , , ,","place":["Frankfurt am Main, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7990-4042","authenticated-orcid":true,"given":"Johanna M. H.","family":"Ehrler","sequence":"additional","affiliation":[{"name":"Goethe University , , ,","place":["Frankfurt am Main, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan S.","family":"Kramer","sequence":"additional","affiliation":[{"name":"Goethe University , , ,","place":["Frankfurt am Main, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Goethe University , , ,","place":["Frankfurt am Main, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Al-Tarrass","sequence":"additional","affiliation":[{"name":"Univ Rouen Normandie , , ,","place":["Rouen, France, F-76000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony","family":"Pereira","sequence":"additional","affiliation":[{"name":"CHU Rouen , , ,","place":["Rouen, France, F-76000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"Valet","sequence":"additional","affiliation":[{"name":"Univ Rouen Normandie , , ,","place":["Rouen, France, F-76000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vale\u0301ry","family":"Brunel","sequence":"additional","affiliation":[{"name":"CHU Rouen , , ,","place":["Rouen, France, F-76000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Schubert-Zsilavecz","sequence":"additional","affiliation":[{"name":"Goethe University , , ,","place":["Frankfurt am Main, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5995-6494","authenticated-orcid":true,"given":"Stefan","family":"Knapp","sequence":"additional","affiliation":[{"name":"Goethe University , , ,","place":["Frankfurt am Main, Germany, 60438"]},{"name":"Buchmann Institute for Molecular Life Sciences (BMLS) , , ,","place":["Frankfurt am Main, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix F.","family":"Lillich","sequence":"additional","affiliation":[{"name":"Goethe University , , ,","place":["Frankfurt am Main, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4064-1473","authenticated-orcid":true,"given":"Victor","family":"Hernandez-Olmos","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP , ,","place":["Frankfurt am Main, Germany, 60596"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8730-284X","authenticated-orcid":true,"given":"Thomas","family":"Duflot","sequence":"additional","affiliation":[{"name":"Univ Rouen Normandie , , ,","place":["Rouen, France, F-76000"]},{"name":"CHU Rouen , , ,","place":["Rouen, France, F-76000"]},{"name":"CHU Rouen , , ,","place":["Rouen, France, F-76000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5458-816X","authenticated-orcid":true,"given":"Kerstin","family":"Hiesinger","sequence":"additional","affiliation":[{"name":"Goethe University , , ,","place":["Frankfurt am Main, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwu","family":"Qian","sequence":"additional","affiliation":[{"name":"University of Science and Technology of China , , ,","place":["Hefei, China, 230027"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Proschak","sequence":"additional","affiliation":[{"name":"Goethe University , , ,","place":["Frankfurt am Main, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Bellien","sequence":"additional","affiliation":[{"name":"Univ Rouen Normandie , , ,","place":["Rouen, France, F-76000"]},{"name":"CHU Rouen , , ,","place":["Rouen, France, F-76000"]},{"name":"CHU Rouen , , ,","place":["Rouen, France, F-76000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1961-1859","authenticated-orcid":true,"given":"Ewgenij","family":"Proschak","sequence":"additional","affiliation":[{"name":"Goethe University , , ,","place":["Frankfurt am Main, Germany, 60438"]},{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP , ,","place":["Frankfurt am Main, Germany, 60596"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"issue":"4","key":"2026082208554168800_cit1","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1124\/pr.113.007781","article-title":"The Pharmacology\nof the Cytochrome P450 Epoxygenase\/Soluble Epoxide Hydrolase Axis\nin the Vasculature and Cardiovascular Disease","volume":"66","author":"Fleming","year":"2014","journal-title":"Pharmacol. 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Lipid\nRes."},{"issue":"4","key":"2026082208554168800_cit10","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1016\/j.bbrc.2012.02.108","article-title":"Role of Soluble Epoxide Hydrolase\nPhosphatase Activity\nin the Metabolism of Lysophosphatidic Acids","volume":"419","author":"Morisseau","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"issue":"1","key":"2026082208554168800_cit11","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.dmpk.2014.09.002","article-title":"The Metabolism\nof Lysophosphatidic\nAcids by Allelic Variants of Human Soluble Epoxide Hydrolase","volume":"30","author":"Purba","year":"2015","journal-title":"Drug Metab. Pharmacokinet."},{"key":"2026082208554168800_cit12","doi-asserted-by":"publisher","first-page":"2980","DOI":"10.1002\/1873-3468.14984","article-title":"Mice Deficient in the\nPhosphatase Activity of sEH Show Decreased Levels of the Endocannabinoid\n2-AG in the Olfactory Bulb and Depressive-like Behavior","volume":"598","author":"Oguro","year":"2024","journal-title":"FEBS Lett."},{"key":"2026082208554168800_cit13","doi-asserted-by":"publisher","first-page":"13524","DOI":"10.1038\/srep13524","article-title":"Role of\nPhosphatase Activity of Soluble Epoxide Hydrolase in Regulating Simvastatin-Activated\nEndothelial Nitric Oxide Synthase","volume":"5","author":"Hou","year":"2015","journal-title":"Sci. Rep."},{"issue":"1","key":"2026082208554168800_cit14","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/j.bbrc.2005.12.180","article-title":"Effects of Human Soluble Epoxide Hydrolase Polymorphisms\non Isoprenoid Phosphate Hydrolysis","volume":"341","author":"Enayetallah","year":"2006","journal-title":"Biochem.\nBiophys. Res. 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Biol."},{"issue":"8","key":"2026082208554168800_cit28","doi-asserted-by":"publisher","first-page":"1288","DOI":"10.1021\/acsmedchemlett.1c00276","article-title":"Rapid Evaluation of Small Molecule\nCellular Target Engagement with a Luminescent Thermal Shift Assay","volume":"12","author":"Mortison","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"issue":"13","key":"2026082208554168800_cit29","doi-asserted-by":"publisher","first-page":"13728","DOI":"10.1021\/acs.jmedchem.5c00552","article-title":"Structure-Based\nDesign of PROTACS for the Degradation of Soluble Epoxide Hydrolase","volume":"68","author":"Scho\u0308nfeld","year":"2025","journal-title":"J. Med. Chem."},{"key":"2026082208554168800_cit30","doi-asserted-by":"publisher","first-page":"S225","DOI":"10.1194\/jlr.R800055-JLR200","article-title":"Lipid Phosphate Phosphatases and\nSignaling","volume":"50","author":"Brindley","year":"2009","journal-title":"J. Lipid Res."},{"issue":"5","key":"2026082208554168800_cit31","doi-asserted-by":"publisher","first-page":"2891","DOI":"10.1074\/jbc.M608057200","article-title":"Compensatory Mechanism\nfor Homeostatic\nBlood Pressure Regulation in Ephx2 Gene-Disrupted Mice","volume":"282","author":"Luria","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2026082208554168800_cit32","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.jare.2022.03.004","article-title":"CRISPR\/Cas9-Mediated Inactivation\nof the Phosphatase Activity of Soluble Epoxide Hydrolase Prevents\nObesity and Cardiac Ischemic Injury","volume":"43","author":"Leuillier","year":"2023","journal-title":"J. Adv.\nRes."},{"issue":"4","key":"2026082208554168800_cit33","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1021\/acschembio.3c00017","article-title":"PROTAC-Mediated\nSelective Degradation of Cytosolic\nSoluble Epoxide Hydrolase Enhances ER Stress Reduction","volume":"18","author":"Wang","year":"2023","journal-title":"ACS Chem. Biol."},{"issue":"11","key":"2026082208554168800_cit34","doi-asserted-by":"publisher","first-page":"1891","DOI":"10.1021\/acsmedchemlett.4c00357","article-title":"In Vivo-Active\nSoluble Epoxide Hydrolase-Targeting\nPROTACs with Improved Potency and Stability","volume":"15","author":"Nakane","year":"2024","journal-title":"ACS Med. Chem. Lett."},{"issue":"92","key":"2026082208554168800_cit35","doi-asserted-by":"publisher","first-page":"18108","DOI":"10.1039\/D5CC03325J","article-title":"Click Chemistry\nEnables Rapid Development of Potent sEH PROTACs Using a Direct-to-Biology\nApproach","volume":"61","author":"Scho\u0308nfeld","year":"2025","journal-title":"Chem. Commun."},{"issue":"23","key":"2026082208554168800_cit36","doi-asserted-by":"publisher","first-page":"17259","DOI":"10.1021\/acs.jmedchem.1c01331","article-title":"Structure-Based Design of Dual Partial\nPeroxisome Proliferator-Activated Receptor \u03b3 Agonists\/Soluble\nEpoxide Hydrolase Inhibitors","volume":"64","author":"Lillich","year":"2021","journal-title":"J. Med. Chem."},{"issue":"15","key":"2026082208554168800_cit37","doi-asserted-by":"publisher","first-page":"3272","DOI":"10.1021\/bi200178z","article-title":"A Versatile and Efficient\nHigh-Throughput Cloning Tool\nfor Structural Biology","volume":"50","author":"Geertsma","year":"2011","journal-title":"Biochemistry"},{"key":"2026082208554168800_cit38","doi-asserted-by":"publisher","first-page":"115191","DOI":"10.1016\/j.bcp.2022.115191","article-title":"Compilation\nand Evaluation of a Fatty Acid Mimetics Screening Library","volume":"204","author":"Ehrler","year":"2022","journal-title":"Biochem. Pharmacol."},{"key":"2026082208554168800_cit39","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/j.bioorg.2018.07.014","article-title":"Discovery of Polar Spirocyclic Orally Bioavailable\nUrea Inhibitors of Soluble Epoxide Hydrolase","volume":"80","author":"Lukin","year":"2018","journal-title":"Bioorg. Chem."},{"issue":"5","key":"2026082208554168800_cit40","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1038\/s41589-025-02121-w","article-title":"Structural Basis for the Catalytic\nMechanism of Human Lipid Phosphate Phosphatases","volume":"22","author":"Yang","year":"2026","journal-title":"Nat. Chem. Biol."},{"issue":"1","key":"2026082208554168800_cit41","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.ab.2006.04.045","article-title":"Development\nof a High-Throughput Screen for Soluble Epoxide Hydrolase Inhibition","volume":"355","author":"Wolf","year":"2006","journal-title":"Anal. Biochem."},{"issue":"11","key":"2026082208554168800_cit42","doi-asserted-by":"publisher","first-page":"784","DOI":"10.3390\/metabo11110784","article-title":"Preventing the Increase in Lysophosphatidic\nAcids:\nA New Therapeutic Target in Pulmonary Hypertension?","volume":"11","author":"Duflot","year":"2021","journal-title":"Metabolites"}],"container-title":["ACS Chemical Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acschembio.6c00502","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acbcct\/article-pdf\/21\/8\/2053\/66319958\/acschembio.6c00502.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acbcct\/article-pdf\/21\/8\/2053\/66319958\/acschembio.6c00502.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T12:55:48Z","timestamp":1787403348000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acbcct\/article\/21\/8\/2053\/5236160\/Fragment-Based-Discovery-of-Fenamic-Acids-as-Pan"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":42,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,7,28]]},"published-print":{"date-parts":[[2026,8,21]]}},"URL":"https:\/\/doi.org\/10.1021\/acschembio.6c00502","relation":{},"ISSN":["1554-8929","1554-8937"],"issn-type":[{"value":"1554-8929","type":"print"},{"value":"1554-8937","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,28]]}}}