Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease

Humanity is facing a vast prevalence of neurodegenerative diseases, with Alzheimer’s disease (AD) being the most dominant, without efficacious drugs, and with only a few therapeutic targets identified. In this scenario, we aim to find molecular entities that modulate imidazoline I2 receptors (I2-IRs) that have been pointed out as relevant targets in AD. In this work, we explored structural modifications of well-established I2-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature. We report the synthesis, the affinity in human I2-IRs, the brain penetration capabilities, the in silico ADMET studies, and the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of this new bunch of I2-IR ligands. Selected compounds showed neuroprotective properties and beneficial effects in an in vitro model of Parkinson’s disease, rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine, and showed crucial anti-inflammatory effects in a cellular model of neuroinflammation. After a preliminary pharmacokinetic study, we explored the action of our representative 2-(benzo[b]thiophen-2-yl)-1H-imidazole LSL33 in a mouse model of AD (5xFAD). Oral administration of LSL33 at 2 mg/Kg for 4 weeks ameliorated 5XFAD cognitive impairment and synaptic plasticity, as well as reduced neuroinflammation markers. In summary, this new I2-IR ligand that promoted beneficial effects in a well-established AD mouse model should be considered a promising therapeutic strategy for neurodegeneration

(2-Imidazolin-4-yl)phosphonates: Green Chemistry and Biology Walk Together

2-Imidazoline-containing compounds constitute a valuable class of agents that modulate α2- adrenergic receptors and often show a high affinity for imidazoline I2-receptors (I2-IR). Moreover, 2- imidazolines are an important class of heterocyclic scaffolds found in natural product chemistry, coordination chemistry, and homogeneous catalysis. To meet the demand for 2-imidazolinecontaining compounds, different synthetic approximations were developed. In this work, we describe an efficient and user-friendly synthetic process involving the combination of isocyanidebased multicomponent reaction and microwave heating without the need of anhydrous atmosphere or additional solvents that generates unprecedented (2-imidazolin-4-yl)phosphonates [1]. We assessed the pharmacological profile and selectivity of the prepared compounds upon I2-IR. Owing to the outstanding high I2-IR affinity of one of the prepared compounds and high selectivity devoid to the α2-adrenoceptor of other compounds, markedly better than any described I2-IR ligand to date, (2-imidazolin-4-yl)phosphonates might be considered as a suitable scaffold for designing novel I2-IR ligands [2]. In addition, we demonstrated the effectiveness of two of the new I2-IR ligands in an in vivo female model for cognitive decline (SAMP8), and we analyzed the pathological biomarkers for neurodegeneration. This study is the first experimental evidence that demonstrates the possibility of using this receptor as a target for cognitive impairment [3]. Note, theoretical studies were carried out for designing compounds with enhanced activity and selectivity upon I2-IR based on created 3D-QSAR model. In this work, green chemistry to access an unprecedented scaffold and promising pharmacological results in the neurodegeneration field walked together.The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery, Barcelona, Spain, 15–17 May 201

Exploring the reactivity of bicyclic α-iminophosphonates to access new imidazoline I<inf>2</inf> receptor ligands

Recent studies pointed out the modulation of imidazoline I2 receptors (I2-IR) by selective ligands as a putative strategy to face neurodegenerative diseases. Foregoing the classical 2-imidazoline/imidazole-containing I2-IR ligands, we report a family of bicyclic α-iminophosphonates endowed with high affinity and selectivity upon I2-IR and we advanced a representative compound B06 in preclinical phases. In this paper, we describe the synthetic possibilities of bicyclic α-iminophosphonates by exploring its ambivalent reactivity, leading to unprecedented molecules that showed promising activities as I2-IR ligands in human brain tissues and good BBB permeation capabilities. After in silico ADME prediction studies, we assessed the neuroprotective properties of selected compounds and beneficial effect in an in vitro model of Alzheimeŕs and Parkinson's disease. Along with their neuroprotective effect, compounds showed a potent anti-inflammatory response when evaluated in a neuroinflammation cellular model. Moreover, this is the first time that the neuroprotective effects of imidazoline I2-IR ligands in a transgenic Alzheimer's disease Caenorhabditis elegans strain are investigated. Using a thrashing assay, we found a significant cognition improvement in this in vivo model after treatment with the new bicyclic α-phosphoprolines. Therefore, our results confirmed the need of exploring structurally new I2-IR ligands and their potential for therapeutic strategies in neurodegeneration.This work was supported by Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (Spain, PID2019-107991RB-I00, PID2022-1380790B-I00), Basque Government (IT-1211-19 and 1512-22), Generalitat de Catalunya (GC) (2021 SGR 00357) and PDC2022-133441-I00 (MCIN/AEI/ 10.13039/501100011033 and by the “European Union NextGenerationEU/PRTR) and by UCM-Santander (PR44/21-29931 to J.A.M.-G.). The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434) under agreement CI18-00002. This activity has received funding from the European Institute of Innovation and Technology (EIT). This body of the European Union receives support from the European Union’s Horizon 2020 research and innovation programme.With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).Peer reviewe

Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice

As populations increase their life expectancy, age-related neurodegenerative disorders such as Alzheimer's disease have become more common. I2-Imidazoline receptors (I2-IR) are widely distributed in the central nervous system, and dysregulation of I2-IR in patients with neurodegenerative diseases has been reported, suggesting their implication in cognitive impairment. This evidence indicates that high-affinity selective I2-IR ligands potentially contribute to the delay of neurodegeneration. In vivo studies in the female senescence accelerated mouse-prone 8 mice have shown that treatment with I2-IR ligands, MCR5 and MCR9, produce beneficial effects in behavior and cognition. Changes in molecular pathways implicated in oxidative stress, inflammation, synaptic plasticity, and apoptotic cell death were also studied. Furthermore, treatments with these I2-IR ligands diminished the amyloid precursor protein processing pathway and increased Aβ degrading enzymes in the hippocampus of SAMP8 mice. These results collectively demonstrate the neuroprotective role of these new I2-IR ligands in a mouse model of brain aging through specific pathways and suggest their potential as therapeutic agents in brain disorders and age-related neurodegenerative diseases. Keywords Imidazoline I2 receptors (2-imidazolin-4-yl)phosphonates Behavior Cognition Neurodegeneration Neuroprotection Agin

Synthesis of nitrogenated compounds with potential interest for the treatment of Unmet Medical Needs

[eng] The synthesis of heterocyclic organic compounds allows access to a wide arsenal of compounds with potential pharmacological activity. This Thesis is part of the field of pharmaceutical chemistry, developing new therapeutic strategies through the design, synthesis and pharmacological evaluation of various families of compounds aimed at treating diseases that currently do not have a therapeutic solution. In the first chapter, the steps followed for the development, in its preclinical phase, of a representative compound that was the object of intellectual protection by the Fundació Bosch i Gimpera (UB) are explained. In the second chapter, the synthetic studies resulting from the exploration of the reactivity of different positions of the family of bicyclic α-iminophosphonates are exposed, which have allowed access to new structures that have been subjected to pharmacological evaluation. Specifically, it has been possible to access a family of compounds that have shown a very relevant biological activity and with potential application to Alzheimer's disease, whose diffusion will be preserved as it is being evaluated for intellectual protection by of the Bosch i Gimpera Foundation. In the third chapter, the synthetic studies resulting from the in-depth study of a multicomponent reaction that has given rise to a family of compounds with antiproliferative activity in a glioblastoma cell line are presented. This activity is similar to that of the drug used in the first line of treatment and, therefore, preliminary studies have been carried out that have made it possible to characterize the representative compound, promoting its development at the preclinical level. In the fourth chapter, a family of compounds that inhibit an enzyme directly related to inflammatory processes is provided. This new family has improved metabolic characteristics compared to previous families developed in the group and that were the subject of intellectual protection. The fifth chapter includes results derived from joint work with collaborating research groups, aimed at finding new applications for both compounds already previously published by us, with which we continue to work, and new compounds that we are developing.[spa] La síntesis de compuestos orgánicos heterocíclicos permite acceder a un amplio arsenal de compuestos con potencial actividad farmacológica. El presente manuscrito se enmarca en el campo de la química farmacéutica, desarrollando nuevas estrategias terapéuticas mediante el diseño, síntesis y evaluación farmacológica de diversas familias de compuestos orientadas al tratamiento de enfermedades que no tienen una solución terapéutica actualmente. Después de una recopilación publicaciones y congresos en los que se ha realizado difusión de los resultados, en la introducción se comenta cuál es la problemática en relación a las enfermedades no cubiertas farmacológicamente y las posibles soluciones y, se comentan los objetivos que han guiado el trabajo realizado en los 5 capítulos que componen la Tesis. En el primer capítulo, se explican los pasos seguidos para el desarrollo, en su fase preclínica, de un compuesto representativo que fue objeto de protección intelectual por parte de la Fundació Bosch i Gimpera (UB). En el segundo capítulo, se exponen los estudios sintéticos resultantes de la exploración de la reactividad de diferentes posiciones de la familia de α-iminofosfonatos bicíclios que han permitido acceder a nuevas estructuras que han sido sometidas a evaluación farmacológica. En concreto, se ha podido acceder a una familia de compuestos que han mostrado una actividad biológica muy relevante y con potencial aplicación a la enfermedad de Alzheimer, de la que se preservará su difusión por estar siendo objeto de evaluación para la su protección intelectual por parte de la Fundación Bosch i Gimpera. En el tercer capítulo, se presentan los estudios sintéticos resultantes del estudio en profundidad de una reacción multicomponente que ha dado lugar a una familia de compuestos con actividad antiproliferativa en una línea celular de glioblastoma. Esta actividad es similar a la del fármaco que se utiliza en la primera línea de tratamiento y, por tanto, se han realizado estudios preliminares que han permitido caracterizar el compuesto representativo propulsando su desarrollo a nivel preclínico. En el cuarto capítulo se aporta una familia de compuestos inhibidores de una enzima directamente relacionada con procesos inflamatorios. Esta nueva familia posee unas características metabólicas mejoradas respecto a familias anteriores desarrolladas en el grupo y que fueron objeto de protección intelectual. En el quinto capítulo, se incluyen resultados derivados del trabajo conjunto con grupos de investigación colaboradores, orientados a la búsqueda de nuevas aplicaciones tanto de compuestos ya publicados previamente por nosotros, con los que seguimos trabajando, como nuevos compuestos que estamos desarrollando. Al final de la memoria, en una sección anexa, se adjuntan publicaciones en revistas del ámbito de la química médica y farmacología de las que soy coautora pero que no son el objetivo principal de la Tesis. Es importante destacar que la Tesis recoge un trabajo multidisciplinar en el que han participado grupos de investigación muy relevantes a nivel nacional e internacional y diversas instituciones

Serum levels of RANKL and OPG, and the RANKL/OPG ratio in bisphosphonate-related osteonecrosis of the jaw: Are they useful biomarkers for the advanced stages of osteonecrosis?

We determined whether serum levels of Receptor Activator for Nuclear Factor κ B Ligand (RANKL), Osteoprotegerin (OPG), and the RANKL/OPG ratio could be useful biomarkers for the severity of oral lesions in bisphosphonate-related osteonecrosis of the jaw (BRONJ). A case-control study in which Group 1 consisted of 41 patients with BRONJ due to bisphosphonates, and Group 2 consisted of 44 healthy control cases. The plasma levels of RANKL and OPG were analyzed by an ELISA assay. The OPG/RANKL ratio was also calculated. We determined if the mean serum values differed among the different stages of BRONJ. Serum levels of RANKL were lower in Group 1 than in Group 2 (p =0.01), and serum levels of OPG were higher in patients with BRONJ than in the controls (p =0.006). The ratio of RANKL/OPG was greater in the controls than in Group 1 (p >0.01). There were no significant differences in the serum levels of RANKL and OPG among the different stages of osteonecrosis (p >0.05). Serum levels of RANKL and OPG, and the RANKL/OPG ratio were not valuable biomarkers for determining the severity of oral lesions in patients with BRONJ.Sin financiación1.671 JCR (2017) Q2, 41/91 Dentistry, Oral Surgery and MedicineUE

Effect of clinical and histologic features on time to malignancy in 224 cases of oral leukoplakia treated by surgery

Objectives Our main purpose and research question were to analyze and quantify whether there were significant differences in the time to develop cancer among patients with oral leukoplakia (OL), comparing the more susceptible cases to those with the least susceptibility to malignancy. Materials and methods We followed 224 cases of OL after surgical or CO2 laser treatment for a mean time of 6.4 years. A Bayesian mixture cure model based on the Weibull distribution was used to model the relationship between our variables and cancer risk. In this model type, the population is considered a mixture of individuals who are susceptible or non-susceptible to developing cancer. The statistical model estimates the probability of cure (incidence model) and then infers the time to malignancy. The model was adjusted using the R-package INLA using default priors. Results Histology type (moderate or severe dysplasia) and tongue location showed hazard ratios (HR) of 3.19 (95% CI [1.05–8.59]) and 4.78 (95% CI [1.6–16.61]), respectively. Both variables increased the risk of malignant transformation, thus identifying a susceptible subpopulation with reduced time required to develop cancer, as with non-homogeneous leukoplakias. The median time for cancer development was 4 years and 5 months, with a minimum of 9 months after the diagnosis of OL and a maximum of 15 years and 2 months. Conclusions Susceptible patients with non-homogeneous leukoplakia, dysplasia, or leukoplakia in the tongue develop cancer earlier than those with homogeneous OL and those without dysplasia. Clinical relevance The novel contribution of this research is that, until now, the time it took for oral leukoplakias to develop cancer based on whether they were homogeneous or non-homogeneous, and if they have or not epithelial dysplasia, had not been comparatively described and quantified. As a final result, the time to malignant transformation in non-homogeneous and dysplastic leukoplakias is significantly shorter.Sin financiación3.607 Q2 JCR 20210.923 Q1 SJR 2021No data IDR 2021UE

Hydrophobic Waters in Bromodomains

Targeting epigenetic proteins is a rapidly growing area for medicinal chemistry and drug [...

A new family of subnanomolar inhibitors of soluble epoxide hydrolase

Trabajo presentado en el ASPET Annual Meeting at Experimental Biology 2022, celebrado en Philadelphia, PA (Estados Unidos), del 2 al 5 de abril de 2022Epoxyeicosatrienoic 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 the corresponding dihydroxyeicosatrienoic acids (DHETs), whereby the biological effects of EETs are diminished, eliminated, or altered.1 Therefore, inhibition of sEH has been suggested as a novel pharmacological approach for the treatment of pain-related disorders and various inflammatory diseases, and a few sEH inhibitors (sEHI) have reached clinical trialsThis research was funded by Grants PID2020-118127RB-I00 and PID2019-107991RB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and by “ERDF A way of making Europe” to S.V. and C.E. Financial support from Generalitat de Catalunya (2017 SGR106) and 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 R01DK103616 to B.D.H

Sex differences in the antidepressant-like response and molecular events induced by the imidazoline-2 receptor agonist CR4056 in rats

In searching for novel targets to design antidepressants, among the characterized imidazoline receptors (IR), I2 receptors are an innovative therapeutical approach since they are dysregulated in major depressive disorder and by classical antidepressant treatments. In fact, several I2 agonists have been characterized for their antidepressant-like potential, but the results in terms of efficacy were mixed and exclusively reported in male rodents. Since there are well-known sex differences in antidepressant-like efficacy, this study characterized the potential effects induced by two I2 drugs, CR4056 (i.e., most promising drug already in phase II clinical trial for its analgesic properties) and B06 (a compound from a new family of bicyclic α-iminophosphonates) under the stress of the forced-swim test in male and female rats exposed to early-life stress. Moreover, some hippocampal neuroplasticity markers related to the potential effects observed were also evaluated (i.e., FADD, p-ERK/ERK, mBDNF, cell proliferation: Ki-67 + cells). The main results replicated the only prior study reporting the efficacy of CR4056 in male rats, while providing new data on its efficacy in females, which was clearly dependent on prior early-life stress exposure. Moreover, B06 showed no antidepressant-like effects in male or female rats. Finally, CR4056 increased FADD content and decreased cell proliferation in hippocampus, without affecting p- ERK/t-ERK ratio and/or mBDNF content. Interestingly, these effects were exclusively observed in female rats, and independently of early-life conditions, suggesting some distinctive molecular underpinnings participating in the therapeutic response of CR4056 for both sexes. In conjunction, these results present CR4056 with an antidepressant-like potential, especially in female rats exposed to stress early in life, together with some neuronal correlates described in the context of these behavioral changes in females