Corpas R

References (4)

Title : Synthesis, In Vitro Profiling, and In Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors - Codony_2022_J.Med.Chem_65_13660
Author(s) : Codony S , Entrena JM , Calvo-Tusell C , Jora B , Gonzalez-Cano R , Osuna S , Corpas R , Morisseau C , Perez B , Barniol-Xicota M , Grinan-Ferre C , Perez C , Rodriguez-Franco MI , Martinez AL , Loza MI , Pallas M , Verhelst SHL , Sanfeliu C , Feixas F , Hammock BD , Brea J , Cobos EJ , Vazquez S
Ref : Journal of Medicinal Chemistry , 65 :13660 , 2022
Abstract : 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.
ESTHER : Codony_2022_J.Med.Chem_65_13660
PubMedSearch : Codony_2022_J.Med.Chem_65_13660
PubMedID: 36222708

Title : Neuroprotective Epigenetic Changes Induced by Maternal Treatment with an Inhibitor of Soluble Epoxide Hydrolase Prevents Early Alzheimer's Disease Neurodegeneration - Bartra_2022_Int.J.Mol.Sci_23_
Author(s) : Bartra C , Irisarri A , Villoslada A , Corpas R , Aguirre S , Garcia-Lara E , Sunol C , Pallas M , Grinan-Ferre C , Sanfeliu C
Ref : Int J Mol Sci , 23 : , 2022
Abstract : Modulation of Alzheimer's disease (AD) risk begins early in life. During embryo development and postnatal maturation, the brain receives maternal physiological influences and establishes epigenetic patterns that build its level of resilience to late-life diseases. The soluble epoxide hydrolase inhibitor N-[1-(1-oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl] urea (TPPU), reported as ant-inflammatory and neuroprotective against AD pathology in the adult 5XFAD mouse model of AD, was administered to wild-type (WT) female mice mated to heterozygous 5XFAD males during gestation and lactation. Two-month-old 5XFAD male and female offspring of vehicle-treated dams showed memory loss as expected. Remarkably, maternal treatment with TPPU fully prevented memory loss in 5XFAD. TPPU-induced brain epigenetic changes in both WT and 5XFAD mice, modulating global DNA methylation (5-mC) and hydroxymethylation (5-hmC) and reducing the gene expression of some histone deacetylase enzymes (Hdac1 and Hdac2), might be on the basis of the long-term neuroprotection against cognitive impairment and neurodegeneration. In the neuropathological analysis, both WT and 5XFAD offspring of TPPU-treated dams showed lower levels of AD biomarkers of tau hyperphosphorylation and microglia activation (Trem2) than the offspring of vehicle-treated dams. Regarding sex differences, males and females were similarly protected by maternal TPPU, but females showed higher levels of AD risk markers of gliosis and neurodegeneration. Taken together, our results reveal that maternal treatment with TPPU impacts in preventing or delaying memory loss and AD pathology by inducing long-term modifications in the epigenetic machinery and its marks.
ESTHER : Bartra_2022_Int.J.Mol.Sci_23_
PubMedSearch : Bartra_2022_Int.J.Mol.Sci_23_
PubMedID: 36499477

Title : From the Design to the In Vivo Evaluation of Benzohomoadamantane-Derived Soluble Epoxide Hydrolase Inhibitors for the Treatment of Acute Pancreatitis - Codony_2021_J.Med.Chem__
Author(s) : Codony S , Calvo-Tusell C , Valverde E , Osuna S , Morisseau C , Loza MI , Brea J , Perez C , Rodriguez-Franco MI , Pizarro-Delgado J , Corpas R , Grinan-Ferre C , Pallas M , Sanfeliu C , Vazquez-Carrera M , Hammock BD , Feixas F , Vazquez S
Ref : Journal of Medicinal Chemistry , : , 2021
Abstract : The pharmacological inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Numerous potent sEH inhibitors (sEHIs) present adamantyl or phenyl moieties, such as the clinical candidates AR9281 or EC5026. Herein, in a new series of sEHIs, these hydrophobic moieties have been merged in a benzohomoadamantane scaffold. Most of the new sEHIs have excellent inhibitory activities against sEH. Molecular dynamics simulations suggested that the addition of an aromatic ring into the adamantane scaffold produced conformational rearrangements in the enzyme to stabilize the aromatic ring of the benzohomoadamantane core. A screening cascade permitted us to select a candidate for an in vivo efficacy study in a murine model of cerulein-induced acute pancreatitis. The administration of 22 improved the health status of the animals and reduced pancreatic damage, demonstrating that the benzohomoadamantane unit is a promising scaffold for the design of novel sEHIs.
ESTHER : Codony_2021_J.Med.Chem__
PubMedSearch : Codony_2021_J.Med.Chem__
PubMedID: 33945278

Title : Pharmacological Inhibition of Soluble Epoxide Hydrolase as a New Therapy for Alzheimer's Disease - Grinan-Ferre_2020_Neurotherapeutics__
Author(s) : Grinan-Ferre C , Codony S , Pujol E , Yang J , Leiva R , Escolano C , Puigoriol-Illamola D , Companys-Alemany J , Corpas R , Sanfeliu C , Perez B , Loza MI , Brea J , Morisseau C , Hammock BD , Vazquez S , Pallas M , Galdeano C
Ref : Neurotherapeutics , : , 2020
Abstract : The inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with 3 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 2 models of age-related cognitive decline and AD using 3 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.
ESTHER : Grinan-Ferre_2020_Neurotherapeutics__
PubMedSearch : Grinan-Ferre_2020_Neurotherapeutics__
PubMedID: 32488482