2-Oxaadamant-1-yl Ureas as Soluble Epoxide Hydrolase Inhibitors: In Vivo Evaluation in a Murine Model of Acute Pancreatitis
| Autor: | Sandra Codony, Concepción Pérez, Santiago Vázquez, Elena Valverde, Elena Sáez, Christophe Morisseau, Manuel Vázquez-Carrera, Bruce D. Hammock, María Isabel Rodríguez-Franco, Rosana Leiva, Sílvia Osuna, Belén Pérez, Ferran Feixas, José Brea, Julen Oyarzabal, Antonio Pineda-Lucena, Eugènia Pujol, M. Isabel Loza, Javier G. Pizarro |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), La Caixa, European Commission, Xunta de Galicia, Fundación Bosch i Gimpera, Universidad de Barcelona, Generalitat de Catalunya, Ministerio de Cultura y Deporte (España) |
| Rok vydání: | 2020 |
| Předmět: |
Adamantane
01 natural sciences chemistry.chemical_compound Mice Catalytic Domain Drug Discovery Urea Enzyme Inhibitors Epoxide Hydrolases 0303 health sciences biology Chemistry Pharmacology and Pharmaceutical Sciences Endoplasmic Reticulum Stress 3. Good health Biochemistry 5.1 Pharmaceuticals Lipophilicity Acute Disease cardiovascular system Molecular Medicine Development of treatments and therapeutic interventions Half-Life Epoxide hydrolase 2 Cell Survival Medicinal & Biomolecular Chemistry Molecular Dynamics Simulation Cell Line 03 medical and health sciences Structure-Activity Relationship Medicinal and Biomolecular Chemistry In vivo Microsomes Animals Humans 030304 developmental biology Binding Sites Animal Endoplasmic reticulum Organic Chemistry Active site In vitro 0104 chemical sciences Rats 010404 medicinal & biomolecular chemistry Pancreatitis Solubility Disease Models Microsome biology.protein Digestive Diseases |
| Zdroj: | Journal of medicinal chemistry, vol 63, iss 17 Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | In vivo pharmacological inhibition of soluble epoxide hydrolase (sEH) reduces inflammatory diseases, including acute pancreatitis (AP). Adamantyl ureas are very potent sEH inhibitors, but the lipophilicity and metabolism of the adamantane group compromise their overall usefulness. Herein, we report that the replacement of a methylene unit of the adamantane group by an oxygen atom increases the solubility, permeability, and stability of three series of urea-based sEH inhibitors. Most of these oxa-analogues are nanomolar inhibitors of both the human and murine sEH. Molecular dynamics simulations rationalize the molecular basis for their activity and suggest that the presence of the oxygen atom on the adamantane scaffold results in active site rearrangements to establish a weak hydrogen bond. The 2-oxaadamantane 22, which has a good solubility, microsomal stability, and selectivity for sEH, was selected for further in vitro and in vivo studies in models of cerulein-induced AP. Both in prophylactic and treatment studies, 22 diminished the overexpression of inflammatory and endoplasmic reticulum stress markers induced by cerulein and reduced the pancreatic damage. This work was funded by the Spanish Ministerio de Economía Industria y Competitividad (grants SAF2017-82771-R to S.V., SAF2015-64146-R, andMICIU/ICTI2017-2020/Referencito M.V.-C., RTI2018-093955-B-C21 to M.I.R.-F., PGC2018-102192-B-I00 to S.O. and RTI2018-101032-J-I00 to F.F.), the CaixaImpulse 2015 Programme, the Spain EIT Health (Proof of concept 2016), the European Regional Development Fund (ERDF),the Xunta de Galicia (GRC2014/011 and ED431C2018-21), the Fundació Bosch i Gimpera, Universitat de Barcelona (F2I grant), the Generalitat de Catalunya (2017 SGR 106, 2017 SGR 124 and 2017 SGR 1707), the Fundacion Fuentes Dutor ́ , the European Research Council (ERC-2015- StG-679001- NetMoDEzyme to S.O.), and the European Community (MSCA-IF-2014-EF-661160-MetAccembly to F.F.). S.C. and E.P. acknowledge PhD fellowships from the Universitat de Barcelona (APIF grants). E.V. and R.L. thank the Institute of Biomedicine of the University of Barcelona (IBUB) and the Spanish Ministerio de Educacion, Cultura y Deporte ́ (FPU grant), respectively, for PhD grants. Partial support was provided by NIH-NIEHS River Award R35 ES03443, NIHNIEHS Superfund Program P42 ES004699, NINDS R01 DK107767, and NIDDK R01 DK103616. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Daniel Closa (IIBB−CSIC, Barcelona, Spain) for advice regarding the histological analyses. |
| Databáze: | OpenAIRE |
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