Soluble Epoxide Hydrolase Inhibitors: Design, Synthesis, in vitro Profiling and in vivo Evaluation in Murine Models of Pain
| Autor: | Vázquez, Santiago, Codony, Sandra, Entrena, José M., Jora, Beatrice, González-Cano, Rafael, Loza, María Isabel, Brea, José, Morisseau, Christophe, Bartra Cabré, Clara, Sanfeliu, Coral, Hammock, Bruce D., Cobos, Enrique J. |
|---|---|
| Přispěvatelé: | Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Bosch i Gimpera, Xunta de Galicia, National Institutes of Health (US), National Institute of Environmental Health Sciences (US), European Commission, Universidad de Barcelona |
| Rok vydání: | 2022 |
| Předmět: | |
| Popis: | Epoxyeicosatrienoic acids (EETs) are endogenous chemical mediators that show anti-inflammatory, antihypertensive, and analgesic effects. Soluble epoxide hydrolase (sEH) converts EETs to their corresponding dihydroxyeicosatrienoic acids, whereby the biological effects of EETs are modified. Therefore, inhibition of sEH has been suggested as a novel pharmacological approach for the treatment of inflammatory and pain-related disorders.1 Recently, we have discovered a new family of sEH inhibitors (sEHI) featuring a unique benzohomoadamantane scaffold. In a murine model of cerulein-induced acute pancreatitis, the administration of a selected candidate significantly reduced pancreatic damage and improved the health status of the animals.2 Herein we report further structure-activity relationships within this series of benzohomoadamantane-derived sEHI. Most of the novel derivatives were endowed with low nanomolar or even subnanomolar IC50 values at the human, murine and rat sEH. Further in vitro profiling (solubility, cytotoxicity, metabolic stability, selectivity, permeability, etc.) and pharmacokinetic studies permitted us to select a candidate for in vivo efficacy studies. This candidate reduced pain in the capsaicin-induced model of allodynia in a dose-dependent manner and outperformed other sEHI tested. In summary, these novel results and the previously reported studies using other families of sEHI, strongly suggest that sEH may be a target of clinical interest for managing pain.3 References: 1-Sun, C.-P.; Zhang, X.-Y.; Morisseau, C.; Hwang, S. H.; Zhang, Z.-J.; Hammock, B. D.; Ma, X.-C. J. Med. Chem. 2021, 64, 184-215. 2-Codony, S.; Calvó-Tusell, C.; Valverde, E.; Osuna, S.; Morisseau, C.; Loza, M.I.; Brea, J.; Pérez, C.; Rodríguez-Franco, M.I.; Pizarro-Delgado, J.; Corpas, R.; Griñán-Ferré, C.; Pallàs, M.; Sanfeliu, C.; Vázquez-Carrera, M.; Hammock, B. D.; Feixas, F.; Vázquez, S. J. Med. Chem., 2021, 64, 5429-5446. 3-McReynolds, C.; Morisseau, C.; Wagner, K.; Hammock, B. D. Adv. Exp. Med. Biol. 2020, 1274, 71-99. This research was funded by Grant PID2020-118127RB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and by “ERDF A way of making Europe” to S.V. Financial support from Fundació Bosch i Gimpera (F2I grant), to S.V., and from the Xunta de Galicia (ED431G 2019/02 and ED431C 2018/21) to M.I.L. are acknowledged. Partial support was provided by NIH-NIEHS River Award R35 ES03443, NIH-NIEHS Superfund Program P42 ES004699, NINDS R01 DK107767, and NIDDK R01 DK103616 to B.D.H. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|