Synthesis, In Vitro Profiling, and In Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors

The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field.Spanish Government SAF2017-82771-R RTI2018-093955-B-C21 PGC2018-102192-B-I00 RTI2018-101032-J-I00 Spanish MCIN/AEIERDF A way of making Europe - MCIN/AEI PID2020-118127RB-I00PID2019-106285RBERDF A way of making EuropeXunta de GaliciaEuropean Commission ED431G 2019/02ED431C 2018/21Fundacio Bosch i GimperaUniversitat de Barcelona (F2I grant) Generalitat de Catalunya 2017 SGR 106 2017 SGR 1707European Research Council (ERC) European Commission ERC-2015-StG-679001-NetMoDEzyme European Commission MSCA-IF-2014-EF661160-MetAccemblyUniversitat de Barcelona (APIF grant)Spanish Society of Medicinal Chemistry (SEQT) and Lilly FWO 12Y0720NMinistry of Science and Innovation, Spain (MICINN) Spanish Government RYC2020-029552-IUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA R35 ES03443 P42 ES004699United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Neurological Disorders & Stroke (NINDS) R01 DK107767 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) R01 DK10361

Descobrint el paper del farmacèutic en persones amb discapacitat visual

Treballs d'Educació Farmacètica als ciutadans. Unitat Docent d'Estades en Pràctiques Tutelades. Facultat de Farmàcia, Universitat de Barcelona. Curs: 2014/2015, Tutores: Dolors Soy i Marian March Pujol.Com a professionals farmacèutics que realitzem atenció centrada als pacients hem d’entendre els reptes als que s’enfronten les persones invidents/amb visió reduïda i realitzar una atenció farmacèutica d’acord a les seves necessitats. L’adherència a la pauta de medicació és difícil per molts pacients, i és fàcil imaginar que es complica encara més quan la visió està afectada. La majoria de pacients invidents no poden distingir el color, el nom, el text de l’embalatge dels medicaments, la graduació d’una xeringa o no poden llegir el prospecte. Com a farmacèutics hem de aprendre a valorar a tots els pacients i veure i desenvolupar estratègies per ajudar-los a millorar el maneig de la medicació

Pharmacological inhibition of soluble epoxide hydrolase protects cognitive impairment in a Niemann-Pick mice model

Niemann-Pick type C (NPC) disease is a childhood autosomal recessive inherited rare neurodegenerative disease characterized by accumulation of cholesterol and glycosphingolipids and where the autophagy-lysosome system and inflammatory processes are implicated in the pathogenesis of the disease. We follow a novel approach to deal with NPC disease, by modulating key features of the disease such as inflammation and autophagy, through inhibition of soluble epoxide hydrolase (sEH)

Soluble epoxide hydrolase inhibitors: design, synthesis, in vitro profiling and in vivo evaluation in murine models of pain

Trabajo presentado en el ASPET Annual Meeting at Experimental Biology 2022, celebrado en Philadelphia, PA (Estados Unidos), del 2 al 5 de abril de 2022This research by the 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, Universitat de Barcelona (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. S.C. acknowledges a PhD fellowship from the Universitat de Barcelona (APIF grant)

Pharmacological Inhibition of Soluble Epoxide Hydrolase as a New Therapy for Alzheimer's Disease

The inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with three compounds in clinical trials. However, the role of this enzyme in the neuroinflammation process has been largely neglected. Herein, we disclose the pharmacological validation of sEH as a novel target for the treatment of Alzheimer's Disease (AD). Evaluation of cognitive impairment and pathological hallmarks were used in two models of age-related cognitive decline and AD using three structurally different and potent sEH inhibitors as chemical probes. sEH is upregulated in brains from AD patients. Our findings supported the beneficial effects of central sEH inhibition, regarding reducing cognitive impairment, neuroinflammation, tau hyperphosphorylation pathology and the number of amyloid plaques. This study suggests that inhibition of inflammation in the brain by targeting sEH is a relevant therapeutic strategy for AD

Synthesis, in Vitro Profiling, and in Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors

The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field

Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer's Disease

With innumerable clinical failures of target-specific drug candidates for multifactorial diseases, such as Alzheimer's disease (AD), which remains inefficiently treated, the advent of multitarget drug discovery has brought a new breath of hope. Here, we disclose a class of 6-chlorotacrine (huprine)‒TPPU hybrids as dual inhibitors of the enzymes soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), a multitarget profile to provide cumulative effects against neuroinflammation and memory impairment. Computational studies confirmed the gorge-wide occupancy of both enzymes, from the main site to a secondary site, including a so far non-described AChE cryptic pocket. The lead compound displayed in vitro dual nanomolar potencies, adequate brain permeability, aqueous solubility, and human microsomal stability and lack of neurotoxicity, and rescued memory, synaptic plasticity and neuroinflammation in an AD mouse model, after low dose chronic oral administration

From the design to the in vivo evaluation of novel soluble epoxide hydrolase inhibitors

[eng] Epoxieicosatrienoic acids acids (EETs) are endogenous chemical mediators derived from arachidonic acid that show anti-inflammatory, antihypertensive, analgesic, angiogenic and antiatherosclerotic effects. Soluble epoxide hydrolase (sEH) converts EETs to their corresponding dihydroxyeicosatrienoic acids, whereby the biological effects of EETs are diminished, eliminated, or altered. Therefore, it has been proposed that inhibition of sEH may have therapeutic effects in various inflammatory and pain-related diseases. A number of very potent sEH inhibitors (sEHIs) have been developed, several of them featuring an adamantane moiety that may account for the low solubility and poor pharmacokinetic profile that have hampered their progress into clinics. In this context, the present thesis has been focused on the design and synthesis of novel sEHIs replacing the adamantane moiety by adamantane-like scaffolds in order to improve their drug- like properties. First, the introduction of an oxygen atom in the adamantane nucleus of known sEHI provided a new family of 2-oxaadamantane-based inhibitors endowed with nanomolar potency and improved aqueous solubility and permeability. A screening cascade was conducted in order to biological characterize the new inhibitors and to select a candidate for the in vivo studies, which revealed that the candidate reduced inflammatory and ER stress markers and diminished the pancreatic damage in a murine model of cerulein-induced acute pancreatitis (AP). Second, the exploration of the size of the lipophilic unit of sEHIs showed that the active center of sEH is flexible and can accommodate both larger and smaller polycycles than adamantane, and that the replacement of the adamantane moiety by larger polycyclic rings led to more potent compounds than the replacement by smaller ones. Taking into account these results, the last step was the development of a new family of sEHIs bearing the benzohomoadamantane scaffold, which features in its structure the synthetically versatile homoadamantane unit fused with an aromatic ring. This new family lead to compounds endowed with excellent inhibitory activities in both human and murine sEH, improved water solubility and microsomal stability. Further in vitro profiling and pharmacokinetic studies allowed us to select different candidates for the in vivo efficacy studies. One of them significantly reduced pancreatic damage and improved the health status of the animals after the induction of AP by cerulein. On the other hand, the compound optimized for the treatment of neuropathic pain fully abolished the capsaicin-induced allodynia and outperformed other sEHI tested. Overall, a plethora of very potent sEHIs endowed with improved DMPK properties that present efficacy in several in vivo murine models have been developed in the present Thesis.[spa] Los ácidos epoxieicosatrienoicos (EETs) son mediadores químicos endógenos derivados del ácido araquidónico que presentan efectos antiinflamatorios, antihipertensivos y analgésicos entre otros, pero son metabolizados rápidamente por la epóxido hidrolasa soluble (sEH), disminuyendo o alterando sus efectos beneficiosos. Así pues, se ha demostrado que la inhibición de la sEH estabiliza los niveles de EETs in vivo y puede tener efectos terapéuticos en diversas enfermedades que cursan con inflamación y dolor. Recientemente se han desarrollado varios inhibidores de la sEH (sEHIs) muy potentes, y muchos de ellos presentan un adamantano en su estructura, hecho que puede explicar su baja solubilidad y su inadecuado perfil farmacocinético. Por este motivo, la presente tesis doctoral se ha centrado en el diseño y síntesis de nuevos sEHIs, reemplazando el anillo de adamantano por policiclos relacionados, para mejorar las propiedades farmacocinéticas de los compuestos existentes. Primero, la introducción de un oxígeno en el núcleo de adamantano dio lugar a una nueva familia de inhibidores que presentaban mejor solubilidad y permeabilidad manteniendo la potencia inhibidora. Se llevó a cabo una cascada de cribaje para seleccionar un candidato para los estudios in vivo, en los que se demostró que reducía los marcadores de inflamación y de estrés del retículo endoplásmico y disminuía el daño pancreático en un modelo murino de pancreatitis aguda (AP). En segundo lugar, la exploración del tamaño de la unidad lipofílica de los sEHIs mostró que el centro activo del enzima es flexible y puede acomodar policiclos más grandes y más pequeños que el adamantano, siendo los más grandes los que mostraban más potencia. Finalmente, se desarrolló una nueva familia de sEHIs con el núcleo de benzohomoadamantano, dando lugar a compuestos extremadamente potentes, mejorando la solubilidad y la estabilidad microsomal de los sEHIs conocidos. Estudios adicionales nos permitieron seleccionar dos candidatos para los estudios in vivo: el primero para el tratamiento de la AP que produjo una reducción del daño pancreático y mejoró del estado de salud de los animales tratados, mientras que el segundo eliminó por completo la alodinia en un modelo predictivo de dolor neuropático. Así pues, en la presente tesis doctoral se han desarrollado diferentes familias de sEHIs muy potentes con propiedades de DMPK mejoradas y se ha demostrado su eficacia en diferentes estudios in vivo