(537.11) Soluble Epoxide Hydrolase Inhibitors: Design, Synthesis, in vitro Profiling and in vivo Evaluation in Murine Models of Pain.

Poster Board Number: B87

Santiago Vázquez (Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Faculty of Pharmacy and Food Sciences, Universitat de Barcelona and IBUB), Sandra Codony (Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Faculty of Pharmacy and Food Sciences, Universitat de Barcelona and IBUB), José Entrena (School of Medicine, University of Granada, and Ibs. Granada), Beatrice Jora (Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Faculty of Pharmacy and Food Sciences, Universitat de Barcelona and IBUB), Rafael González-Cano (School of Medicine, University of Granada, and Ibs. Granada), M. Loza (Drug Screening Platform/Biofarma Research Group, CIMUS Research Center. University of Santiago de Compostela (USC)), Jose Brea (Drug Screening Platform/Biofarma Research Group, CIMUS Research Center. University of Santiago de Compostela (USC), Santiago de Compostela, Spain), Christophe Morisseau (UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA), Clara Bartra (Institut d’Investigacions Biomèdiques de Barcelona (IIBB), CSIC and IDIBAPS, Barcelona, Spain), Coral Sanfeliu (Institut d’Investigacions Biomèdiques de Barcelona (IIBB), CSIC and IDIBAPS, Barcelona, Spain), Bruce Hammock (UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA), Enrique Cobos (Department of Pharmacology, School of Medicine, University of Granada, and Ibs. Granada, Granada, Spain)

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.

Support or Funding Information

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.

This research was funded by Grant PID2020-118127RB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and by amp;ldquo;ERDF A way of making Europeamp;rdquo; to S.V. Financial support from lt;igt;Fundaciamp;oacute; Bosch i Gimperalt;/igt; (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.