Brea J

References (10)

Title : Novel thienocycloalkylpyridazinones as useful scaffolds for acetylcholinesterase inhibition and serotonin 5-HT(6) receptor interaction - Asproni_2023_Bioorg.Med.Chem_84_117256
Author(s) : Asproni B , Catto M , Loriga G , Murineddu G , Corona P , Purgatorio R , Cichero E , Fossa P , Scarano N , Martinez AL , Brea J , Pinna GA
Ref : Bioorganic & Medicinal Chemistry , 84 :117256 , 2023
Abstract : A library of eighteen thienocycloalkylpyridazinones was synthesized for human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibition and serotonin 5-HT(6) receptor subtype interaction by following a multitarget-directed ligand approach (MTDL), as a suitable strategy for treatment of Alzheimer's disease (AD). The novel compounds featured a tricyclic scaffold, namely thieno[3,2-h]cinnolinone, thienocyclopentapyridazinone and thienocycloheptapyridazinone, connected through alkyl chains of variable length to proper amine moieties, most often represented by N-benzylpiperazine or 1-(phenylsulfonyl)-4-(piperazin-1-ylmethyl)-1H-indole as structural elements addressing AChE and 5-HT(6) interaction, respectively. Our study highlighted the versatility of thienocycloalkylpyridazinones as useful architectures for AChE interaction, with several N-benzylpiperazine-based analogues emerging as potent and selective hAChE inhibitors with IC(50) in the 0.17-1.23 microM range, exhibiting low to poor activity for hBChE (IC(50) = 4.13-9.70 microM). The introduction of 5-HT(6) structural moiety phenylsulfonylindole in place of N-benzylpiperazine, in tandem with a pentamethylene linker, gave potent 5-HT(6) thieno[3,2-h]cinnolinone and thienocyclopentapyridazinone-based ligands both displaying hAChE inhibition in the low micromolar range and unappreciable activity towards hBChE. While docking studies provided a rational structural explanation for AChE/BChE enzyme and 5-HT(6) receptor interaction, in silico prediction of ADME properties of tested compounds suggested further optimization for development of such compounds in the field of MTDL for AD.
ESTHER : Asproni_2023_Bioorg.Med.Chem_84_117256
PubMedSearch : Asproni_2023_Bioorg.Med.Chem_84_117256
PubMedID: 37003157

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 : 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 - Codony_2022_J.Med.Chem_65_4909
Author(s) : Codony S , Pont C , Grinan-Ferre C , Di Pede-Mattatelli A , Calvo-Tusell C , Feixas F , Osuna S , Jarne-Ferrer J , Naldi M , Bartolini M , Loza MI , Brea J , Perez B , Bartra C , Sanfeliu C , Juarez-Jimenez J , Morisseau C , Hammock BD , Pallas M , Vazquez S , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 65 :4909 , 2022
Abstract : 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, human microsomal stability, lack of neurotoxicity, and it rescued memory, synaptic plasticity, and neuroinflammation in an AD mouse model, after low dose chronic oral administration.
ESTHER : Codony_2022_J.Med.Chem_65_4909
PubMedSearch : Codony_2022_J.Med.Chem_65_4909
PubMedID: 35271276

Title : 2-(Piperidin-4-yl)acetamides as Potent Inhibitors of Soluble Epoxide Hydrolase with Anti-Inflammatory Activity - Martin-Lopez_2021_Pharmaceuticals.(Basel)_14_
Author(s) : Martin-Lopez J , Codony S , Bartra C , Morisseau C , Loza MI , Sanfeliu C , Hammock BD , Brea J , Vazquez S
Ref : Pharmaceuticals (Basel) , 14 : , 2021
Abstract : The pharmacological inhibition of soluble epoxide hydrolase (sEH) has been suggested as a potential therapy for the treatment of pain and inflammatory diseases through the stabilization of endogenous epoxyeicosatrienoic acids. Numerous potent sEH inhibitors (sEHI) have been developed, however many contain highly lipophilic substituents limiting their availability. Recently, a new series of benzohomoadamantane-based ureas endowed with potent inhibitory activity for the human and murine sEH was reported. However, their very low microsomal stability prevented further development. Herein, a new series of benzohomoadamantane-based amides were synthetized, fully characterized, and evaluated as sEHI. Most of these amides were endowed with excellent inhibitory potencies. A selected compound displayed anti-inflammatory effects with higher effectiveness than the reference sEHI, TPPU.
ESTHER : Martin-Lopez_2021_Pharmaceuticals.(Basel)_14_
PubMedSearch : Martin-Lopez_2021_Pharmaceuticals.(Basel)_14_
PubMedID: 34959721

Title : From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects - Pont_2021_Eur.J.Med.Chem_225_113779
Author(s) : Pont C , Ginex T , Grinan-Ferre C , Scheiner M , Mattellone A , Martinez N , Arce EM , Soriano-Fernandez Y , Naldi M , De Simone A , Barenys M , Gomez-Catalan J , Perez B , Sabate R , Andrisano V , Loza MI , Brea J , Bartolini M , Bolognesi ML , Decker M , Pallas M , Luque FJ , Munoz-Torrero D
Ref : Eur Journal of Medicinal Chemistry , 225 :113779 , 2021
Abstract : Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Abeta42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.
ESTHER : Pont_2021_Eur.J.Med.Chem_225_113779
PubMedSearch : Pont_2021_Eur.J.Med.Chem_225_113779
PubMedID: 34418785

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 : Centrally Active Multitarget Anti-Alzheimer Agents Derived from the Antioxidant Lead CR-6 - Perez-Areales_2020_J.Med.Chem_63_9360
Author(s) : Perez-Areales FJ , Garrido M , Aso E , Bartolini M , De Simone A , Espargaro A , Ginex T , Sabate R , Perez B , Andrisano V , Puigoriol-Illamola D , Pallas M , Luque FJ , Loza MI , Brea J , Ferrer I , Ciruela F , Messeguer A , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 63 :9360 , 2020
Abstract : Oxidative stress is a major pathogenic factor in Alzheimer's disease, but it should not be tackled alone rather together with other key targets to derive effective treatments. The combination of the scaffold of the polar antioxidant lead 7-methoxy-2,2-dimethylchroman-6-ol (CR-6) with that of the lipophilic cholinesterase inhibitor 6-chlorotacrine results in compounds with favorable brain permeability and multiple activities in vitro (acetylcholinesterase, butyrylcholinesterase, beta-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE-1), and Abeta42 and tau aggregation inhibition). In in vivo studies on wild-type and APP/presenilin 1 (PS1) mice, two selected compounds were well tolerated and led to positive trends, albeit statistically nonsignificant in some cases, on memory performance, amyloid pathology (reduced amyloid burden and potentiated non-amyloidogenic APP processing), and oxidative stress (reduced cortical oxidized proteins and increased antioxidant enzymes superoxide dismutase 2 (SOD2), catalase, glutathione peroxidase 1 (GPX1), and heme oxygenase 1 (Hmox1) and transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2)). These compounds emerge as interesting brain-permeable multitarget compounds, with a potential as anti-Alzheimer agents beyond that of the original lead CR-6.
ESTHER : Perez-Areales_2020_J.Med.Chem_63_9360
PubMedSearch : Perez-Areales_2020_J.Med.Chem_63_9360
PubMedID: 32706255

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

Title : Exploring the size of the lipophilic unit of the soluble epoxide hydrolase inhibitors - Codony_2019_Bioorg.Med.Chem_27_115078
Author(s) : Codony S , Valverde E , Leiva R , Brea J , Isabel Loza M , Morisseau C , Hammock BD , Vazquez S
Ref : Bioorganic & Medicinal Chemistry , 27 :115078 , 2019
Abstract : Soluble epoxide hydrolase (sEH) inhibitors are potential drugs for several diseases. Adamantyl ureas are excellent sEH inhibitors but have limited metabolic stability. Herein, we report the effect of replacing the adamantane group by alternative polycyclic hydrocarbons on sEH inhibition, solubility, permeability and metabolic stability. Compounds bearing smaller or larger polycyclic hydrocarbons than adamantane yielded all good inhibition potency of the human sEH (0.4<=IC50<=21.7nM), indicating that sEH is able to accommodate inhibitors of very different size. Human liver microsomal stability of diamantane containing inhibitors is lower than that of their corresponding adamantane counterparts.
ESTHER : Codony_2019_Bioorg.Med.Chem_27_115078
PubMedSearch : Codony_2019_Bioorg.Med.Chem_27_115078
PubMedID: 31488357

Title : Multitarget-directed tricyclic pyridazinones as g protein-coupled receptor ligands and cholinesterase inhibitors - Pau_2015_ChemMedChem_10_1054
Author(s) : Pau A , Catto M , Pinna G , Frau S , Murineddu G , Asproni B , Curzu MM , Pisani L , Leonetti F , Loza MI , Brea J , Pinna GA , Carotti A
Ref : ChemMedChem , 10 :1054 , 2015
Abstract : By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A , adrenergic alpha1A , and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of alpha1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles.
ESTHER : Pau_2015_ChemMedChem_10_1054
PubMedSearch : Pau_2015_ChemMedChem_10_1054
PubMedID: 25924828