Andreea Larisa Turcu

The inhibition of soluble epoxide hydrolase (sEH) has emerged as an attractive therapeutic strategy through the stabilization of endogenous bioactive epoxyeicosatrienoic acids. Most of the inhibitors developed to date contain a central urea pharmacophore; however, these compounds often suffer from physicochemical limitations, particularly limited aqueous solubility. Herein, we report the design, synthesis, and biological evaluation of a new family of 2‐(1‐benzylpiperidin‐4‐yl)acetamides inspired by the reference sEH inhibitor 1‐(1‐propionylpiperidin‐4‐yl)‐3‐(4‐(trifluoromethoxy)phenyl)urea (TPPU). Replacement of the urea pharmacophore in TPPU with an amide significantly improved aqueous solubility but reduced inhibitory potency. Surprisingly, substitution of the trifluoromethyl group of TPPU with a pentafluorosulfanyl substituent restored potency against human sEH, leading to the identification of a promising hit compound. Subsequent structure–activity relationship studies guided by the Topliss Batchwise Scheme (TBS) enabled systematic optimization of the aromatic substitution pattern and revealed that electronic effects are the main drivers of inhibitory potency, leading to several analogs displaying strong activity across human, mouse, and rat sEH. However, their further development was discontinued due to safety‐related liabilities identified during the screening cascade. Nevertheless, these results highlight the utility of the underexplored pentafluorosulfanyl group and the TBS strategy for optimizing amide‐based sEH inhibitors.

The ATP-gated P2X7 receptor (P2X7R) activates inflammatory signaling pathways in the central nervous system. In particular, P2X7Rs drive chronic glia-mediated neuroinflammation, which is increasingly recognized as a key contributor to Alzheimer’s disease, a neurodegenerative disorder that lacks effective disease-modifying therapies. Here we identify a potent and selective negative allosteric modulator of P2X7Rs with therapeutic potential. We synthesize a series of small molecules based on a polycyclic scaffold and confirm blood-brain barrier penetration by testing a radiolabeled analogue using positron emission tomography imaging. Through a structure-guided medicinal chemistry campaign centered on our scaffold, we identify four promising P2X7R antagonists. Of these, UB-ALT-P2 exhibits the most favorable safety profile, high oral bioavailability and robust brain penetration. High-resolution cryo-EM structures of UB-ALT-P2 bound to human, mouse, and rat P2X7Rs reveal a conserved antagonist binding mode with steric features that favor prolonged binding to human receptors. In the 5xFAD mouse model of AD, oral UB-ALT-P2 blunts weight loss, improves short- and long-term memory, reduces amyloid-β plaque burden, lowers hyperphosphorylated tau, and diminishes oxidative and inflammatory markers. These results establish UB-ALT-P2 as a potent and safe P2X7R antagonist that can mitigate core AD pathologies, providing a compelling foundation for further development.

The soluble epoxide hydrolase (sEH) has recently emerged as a promising target for the treatment of several pain-related conditions. Herein, we report the design and synthesis of a peripherally restricted sEH inhibitor with high potency and good Drug Metabolism and Pharmacokinetics (DMPK) properties. Molecular dynamics and X-ray crystallography helped reveal the binding of these inhibitors to sEH. The selected compound showed a robust analgesic effect in a dose-dependent manner in a murine model of chemotherapy-induced neuropathic pain (CINP). Moreover, the compound also prevented the development of paclitaxel-induced neuropathic pain. Overall, these results suggest that peripheral inhibition of sEH might constitute a novel therapy to prevent and treat CINP.

The P2X7 receptor is an ATP-gated ion channel that activates inflammatory pathways involved in diseases such as cancer, atherosclerosis, and neurodegeneration. However, despite the potential benefits of blocking overactive signaling, no P2X7 receptor antagonists have been approved for clinical use. Understanding species-specific pharmacological effects of existing antagonists has been challenging, in part due to the dearth of molecular information on receptor orthologs. Here, to identify distinct molecular features in the human receptor, we determine high-resolution cryo-EM structures of the full-length wild-type human P2X7 receptor in apo closed and ATP-bound open state conformations and draw comparisons with structures of other orthologs. We also report a cryo-EM structure of the human receptor in complex with an adamantane-based inhibitor, which we leverage, in conjunction with functional data and molecular dynamics simulations, to design a potent and selective antagonist with a unique polycyclic scaffold. Functional and structural analysis reveal how this optimized ligand, termed UB-MBX-46, interacts with the classical allosteric pocket of the human P2X7 receptor with subnanomolar potency and high selectivity, revealing its significant therapeutic potential.

The increasing resistance of influenza A viruses to adamantane-based antivirals underscores the need for new inhibitors targeting both wild-type (WT) and mutant M2 ion channels. Here, we report the synthesis and biological evaluation of polycyclic cage amines designed to replace the adamantane scaffold as M2 inhibitors. These include ring-contracted and ring-expanded analogues, evaluated both as primary amines and as aryl-/heteroaryl-substituted derivatives. Most of the polycyclic amines inhibited the WT M2 channel as demonstrated by electrophysiological assays. Among them, compound 10 , a 3,4,8,9-tetramethyltetracyclo[4.4.0.0³.⁶.0⁴.⁸]decan-1-amine, emerged as a triple blocker active against M2 WT, M2 L27F, and M2 V27A channels. In contrast, compound 6c , a noradamantane–isoxazole derivative, showed selective inhibition of the S31N mutant. Although no antiviral activity was observed against influenza A virus in infected cell assays, both compounds 6c and 10 displayed significant antiviral activity against human coronavirus 229E. Furthermore, compound 10 demonstrated favourable pharmacokinetic properties. MD simulations show that noradamantane 6c binds inside the M2 S31N pore, with its ammonium forming H-bonds to Asn31 and the isoxazole positioned near Val27, restricting water entry. In contrast, larger polycyclic amines likely cannot access the pore due to steric hindrance.

Memantine is an US Food and Drug Administration (FDA) approved drug that is thought to selectively inhibit NMDA-subtype of ionotropic glutamate receptors (NMDARs). NMDARs enable calcium influx into neurons and are critical for normal brain function. However, increasing evidence shows that calcium influx in neurological diseases is augmented by calcium-permeable AMPA-subtype ionotropic glutamate receptors (AMPARs). Here, we demonstrate that these calcium-permeable AMPARs (CP-AMPARs) are inhibited by memantine. Electrophysiology unveils that memantine inhibition of CP-AMPARs is dependent on their calcium permeability and the presence of their neuronal auxiliary subunit transmembrane AMPAR regulatory proteins (TARPs). Through cryo-electron microscopy we elucidate that memantine blocks CP-AMPAR ion channels in a unique mechanism of action from NMDARs. Furthermore, we demonstrate that memantine inhibits a gain of function AMPAR mutation found in a patient with a neurodevelopmental disorder. Our findings unlock potential exploitation of this site to design more specific drugs targeting CP-AMPARs.

The P2X7 receptor is an ATP-gated ion channel that activates inflammatory pathways involved in diseases such as cancer, atherosclerosis, and neurodegeneration. However, despite the potential benefits of blocking overactive signaling, no P2X7 receptor antagonists have been approved for clinical use. Interspecies variation among existing antagonists has proven challenging, in part due to the dearth of molecular information on different receptor orthologs. Here, to identify distinct molecular features in the human receptor, we determine high-resolution cryo-EM structures of the full-length wild-type human P2X7 receptor in apo closed and ATP-bound open state conformations and draw comparisons with new and existing structures of other orthologs. We also report a cryo-EM structure of the human receptor in complex with an adamantane-based inhibitor, which we leverage, in conjunction with functional data and molecular dynamics simulations, to design a potent and selective antagonist with a unique polycyclic scaffold. Functional and structural analysis reveal how this optimized ligand, UB-MBX-46, interacts with the classical allosteric pocket of the human P2X7 receptor with picomolar potency and high selectivity, revealing its significant therapeutic potential.

INTRODUCCIÓN. Desde 2015, la Facultad de Farmacia y Ciencias de la Alimentación de la Universidad de Barcelona implementa el programa «Pasaporte a la profesión» para vincular la formación académica del alumnado del grado de Farmacia con el mundo laboral. Este programa enfatiza la experiencia práctica y el desarrollo profesional mediante actividades, a fin de mejorar las oportunidades laborales de los estudiantes y prepararlos para los desafíos profesionales. En este artículo se analiza el progreso, la eficacia, el impacto del programa y sus áreas de mejora. MÉTODO. Se hizo un análisis comparativo utilizando las encuestas de satisfacción recopiladas entre los años 2015 y 2023. El estudio incluyó los datos sobre la evolución de la participación de los estudiantes, la evaluación de las sesiones y la identificación de puntos débiles del programa, entre otros parámetros. RESULTADOS y DISCUSIÓN. Destaca la alta valoración del programa por parte de los participantes, siendo necesarias mejoras en su difusión y en algunas áreas de contenidos. En consecuencia, se ha creado una hoja de ruta para el «Pasaporte a la profesión» con la intención de conseguir que el programa cumpla y supere sus objetivos educativos, adaptándose a las necesidades cambiantes de los estudiantes y del mercado laboral.

Solifenacin (SFC) is a potent muscarinic antagonist that effectively reduces bladder muscle contraction, thereby alleviating symptoms such as frequency of micturition and urgency. Oxidation of SFC leads to the formation of impurities like Impurity K. Effective analysis and control of this impurity is crucial for ensuring compliance with regulatory standards and safeguarding patient health. To address these challenges, we propose a novel one-step synthesis of Impurity K from SFC. Impurity K was synthesized using cerium(IV) ammonium nitrate (CAN) in water/acetonitrile as the solvent. Additionally, we describe a new HPLC-MS method for the detection of Impurity K in solifenacin succinate tablets.

Solifenacin (SFC) is a potent muscarinic antagonist that effectively reduces bladder muscle contraction, thereby alleviating symptoms such as frequency of micturition and urgency. Oxidation of SFC leads to the formation of impurities like Impurity K. Effective analysis and control of this impurity is crucial for ensuring compliance with regulatory standards and safeguarding patient health. To address these challenges, we propose a novel one-step synthesis of Impurity K from SFC. Impurity K was synthesized using cerium ammonium (IV) nitrate (CAN) in water/acetonitrile as the solvent. Additionally, we describe a new HPLC-MS method for the detection of Impurity K in solifenacin succinate tablets.