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We previously reported trisubstituted pyrimidine lead compounds, namely, ARN22089 and ARN25062, which block the interaction between CDC42 with its specific downstream effector, a PAK protein. This interaction is crucial for the progression of multiple tumor types. Such inhibitors showed anticancer efficacy in vivo. Here, we describe a second class of CDC42 inhibitors with favorable drug-like properties. Out of the 25 compounds here reported, compound 15 (ARN25499) stands out as the best lead compound with an improved pharmacokinetic profile, increased bioavailability, and efficacy in an in vivo PDX tumor mouse model. Our results indicate that these CDC42 inhibitors represent a promising chemical class toward the discovery of anticancer drugs, with ARN25499 as an additional lead candidate for preclinical development.
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Antineoplásicos , Proteína de Unión al GTP cdc42 , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/química , Humanos , Ratones , Proteína de Unión al GTP cdc42/antagonistas & inhibidores , Proteína de Unión al GTP cdc42/metabolismo , Línea Celular Tumoral , Descubrimiento de Drogas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto , Pirimidinas/farmacocinética , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , FemeninoRESUMEN
BACKGROUND: We recently demonstrated that 48 h exposure of primary human bronchial epithelial (hBE) cells, obtained from both CF (F508del homozygous) and non-CF subjects, to the triple drug combination Elexacaftor/Tezacaftor/Ivacaftor (ETI) results in a CFTR genotype-independent modulation of the de novo synthethic pathway of sphingolipids, with an accumulation of dihydroceramides (dHCer). Since dHCer are converted into ceramides (Cer) by the action of a delta-4 sphingolipid desaturase (DEGS) enzyme, we aimed to better understand this off-target effect of ETI (i.e., not related to CFTR rescue) METHODS: hBE cells, both F508del and wild-type, were cultured to create fully differentiated bronchial epithelia. We analyzed Cer and dHCer using an LC-MS based method previously developed by our lab. DEGS expression levels in differentiated hBE cells lysates were quantified by western blot analysis. RESULTS: We demonstrated that 1) dHCer accumulate in hBE with time following prolonged ETI exposure, that 2) similar inhibition occurs in wild-type primary human hepatocytes and that 3) this does not result in an alteration of DEGS expression. We then proved that 4) ETI is a direct inhibitor of DEGS, that 5) Tezacaftor is the molecule responsible for this effect, that 6) the inhibition is concentration dependent. Finally, after repeated oral administration of ETI to naïve, non-CF, mice, we observed a slight accumulation of dHCer in the brain. CONCLUSIONS: We believe that further investigations on Tezacaftor should be envisaged, particularly for the use of ETI during pregnancy, breastfeeding and in the early stages of development. DEGS dysfunction and dHCer accumulation causes impairment in the development of the nervous system, due to a derangement in myelin formation and maintenance.
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In this study, hydrogels were produced using a Schiff base reaction between two hyaluronic acid derivatives: one containing aldehyde groups (HA-Ald) and the other holding a diethylenetriamine with terminal amino groups (HA-DETA). The DETA portion promotes the in situ growth, complexation, and stabilization of silver nanoparticles (AgNPs), eliminating the need for external reducing agents. The reaction between HA-DETA and HA-Ald leads to the formation of imine bonds, which results in dynamically pH-responsive cross-linking. While the DETA capping ability helped in embedding the AgNPs, the on/off pH environmental responsivity of the hydrogel allows for a controlled and on-demand release of the drug, mainly when bacterial infections cause pH variation of the wound bed. The injectable hydrogels resulted in being highly compatible in contact with blood red cells, fibroblasts, and keratinocytes and capable of having a proliferative effect on an in vitro wound scratch model. The pH-responsive hydrogels showed proper antibacterial activity againstPseudomonas aeruginosaandStaphylococcus aureus, common bacterial strains presented in wound infections. Finally, in vivo wound model studies demonstrated an overall speeding up in the wound healing rate and advanced wound conditions in the experimental group treated with the hydrogels compared to control samples.
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Glioblastoma accounts almost 50% of all brain cancers, being the most common and lethal brain tumor in adults. Despite the current standard gold treatment based on surgery, chemotherapy, and radiotherapy, other treatment strategies are needed. Different in vitro models are currently used, including commercial cell lines, patient-derived cell lines, organoids, as well as in vivo models, being orthotopic xenografts the most used ones. In this chapter, we describe a standard protocol for the intracranial inoculation of glioblastoma cells in immunodeficient mice, and how to follow up the tumor progression and analyze the data.
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Neoplasias Encefálicas , Glioblastoma , Adulto , Humanos , Ratones , Animales , Glioblastoma/patología , Neoplasias Encefálicas/patología , Línea Celular , Xenoinjertos , Modelos Animales de Enfermedad , Línea Celular TumoralRESUMEN
Diabetes is rising as one of the most diffused diseases of the century with the related urgent necessity to face its systemic and local effects on the patients, such as cardiovascular problems, degeneration of limbs, and dysfunction of the wound healing process. The diffusion of leg ulcers has been estimated to be 1.51 for 1000 population, and these non-resolved wounds can produce several social, economic, and mental health issues in diabetic patients. At the same time, these people experience neuropathic pain that causes morbidity and a further decrease in their quality of life. Here, a new study is presented where asodium alginate/Polyvinylpyrrolidone-Iodine complex (PVPI)-based wound dressing is combined with the Frequency Rhythmic Electrical Modulation System (FREMS) technology, an established medical device for the treatment of neuropathic pain and diabetic ulcers. The produced Alginate/PVPI-based films are characterized in terms of morphology, chemistry, wettability, bio-/hemo-compatibility, and clotting capacity. Next, the Alginate/PVPI-based films are used together with FREMS technology in diabetic mice models, and synergism of their action in the wound closure rate and anti-inflammatory properties is found. Hence, how the combination of electrical neurostimulation devices and advanced wound dressings can be a new approach to improve chronic wound treatment is demonstrated.
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Diabetes Mellitus Experimental , Neuralgia , Humanos , Animales , Ratones , Povidona Yodada/química , Alginatos/química , Calidad de Vida , Diabetes Mellitus Experimental/terapiaRESUMEN
Ureteral stents are among the most frequently used human implants, with urothelium trauma, blood clots, and bacterial colonization being their main reasons for failure. In this study, berberine-loaded zein (ZB) nanoparticles with high drug encapsulation efficiency (>90 %) were fabricated via electrospray on flat and 3D stainless steel structures. Physico-chemical characterization revealed that the ZB nanoparticles created a highly hydrophilic, antioxidant, and scratch-resistant continuous coating over the metal structure. Results showed that the drug release rate was faster at neutral pH (i.e., PBS pH 7.4) than in an artificial urine medium (pH 5.3) due to the different swelling behavior of the zein polymeric matrix. In vitro evaluation of ZB particles onto human dermal fibroblasts and blood cells demonstrated good cell proliferation and enhanced anti-thrombotic properties compared to bare stainless steel. The ability of the electrosprayed zein particles to resist bacterial adherence and proliferation was evaluated with Gram-negative (Escherichia coli) bacteria, showing high inhibition rates (-29 % and -46 % for empty and berberine-loaded particles, respectively) compared to the medical-grade metal substrates. Overall, the proposed composite coating fulfilled the requirements for ureteral applications, and can advance the development of innovative biocompatible, biodegradable, and antibacterial coatings for drug-eluting stents.
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Berberina , Nanopartículas , Zeína , Humanos , Zeína/química , Acero Inoxidable , Antibacterianos/farmacología , Stents , Nanopartículas/química , MetalesRESUMEN
Neurodegenerative processes characterizing Alzheimer's disease (AD) are strictly related to the impairment of cholinergic and glutamatergic neurotransmitter systems which provoke synaptic loss. These experimental evidences still represent the foundation of the actual standard-of-care treatment for AD, albeit palliative, consisting on the coadministration of an acetylcholinesterase inhibitor and the NMDAR antagonist memantine. In looking for more effective treatments, we previously developed a series of galantamine-memantine hybrids where compound 1 (ARN14140) emerged with the best-balanced action toward the targets of interest paired to neuroprotective efficacy in a murine AD model. Unfortunately, it showed a suboptimal pharmacokinetic profile, which required intracerebroventricular administration for in vivo studies. In this work we designed and synthesized new hybrids with fewer rotatable bonds, which is related to higher brain exposure. Particularly, compound 2, bearing a double bond in the tether, ameliorated the biological profile of compound 1 in invitro studies, increasing cholinesterases inhibitory potencies and selective antagonism toward excitotoxic-related GluN1/2B NMDAR over beneficial GluN1/2A NMDAR. Furthermore, it showed increased plasma stability and comparable microsomal stability in vitro, paired with lower half-life and faster clearance in vivo. Remarkably, pharmacokinetic evaluations of compound 2 showed a promising increase in brain uptake in comparison to compound 1, representing the starting point for further chemical optimizations.
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Enfermedad de Alzheimer , Galantamina , Humanos , Ratones , Animales , Galantamina/farmacocinética , Memantina/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Acetilcolinesterasa , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Receptores de N-Metil-D-AspartatoRESUMEN
Glioblastoma multiforme (GBM) is a devastating tumor of the central nervous system, currently missing an effective treatment. The therapeutic gold standard consists of surgical resection followed by chemotherapy (usually with temozolomide, TMZ) and/or radiotherapy. TMZ does not, however, provide significant survival benefit after completion of treatment because of development of chemoresistance and of heavy side effects of systemic administration. Improvement of conventional treatments and complementary therapies are urgently needed to increase patient survival and quality of life. Stimuli-responsive lipid-based drug delivery systems offer promising prospects to overcome the limitations of the current treatments. In this work, multifunctional lipid-based magnetic nanovectors functionalized with the peptide angiopep-2 and loaded with TMZ (Ang-TMZ-LMNVs) were tested to enhance specific GBM therapy on an in vivo model. Exposure to alternating magnetic fields (AMFs) enabled magnetic hyperthermia to be performed, that works in synergy with the chemotherapeutic agent. Studies on orthotopic human U-87 MG-Luc2 tumors in nude mice have shown that Ang-TMZ-LMNVs can accumulate and remain in the tumor after local administration without crossing over into healthy tissue, effectively suppressing tumor invasion and proliferation and significantly prolonging the median survival time when combined with the AMF stimulation. This powerful synergistic approach has proven to be a robust and versatile nanoplatform for an effective GBM treatment.
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Glioblastoma , Hipertermia Inducida , Nanopartículas de Magnetita , Animales , Ratones , Humanos , Glioblastoma/tratamiento farmacológico , Nanopartículas de Magnetita/uso terapéutico , Ratones Desnudos , Calidad de Vida , Temozolomida/farmacología , LípidosRESUMEN
Natural polymers from organic wastes have gained increasing attention in the biomedical field as resourceful second raw materials for the design of biomedical devices which can perform a specific bioactive function and eventually degrade without liberating toxic residues in the surroundings. In this context, patches and bandages, that need to support the skin wound healing process for a short amount of time to be then discarded, certainly constitute good candidates in our quest for a more environmentally friendly management. Here, we propose a plant-based microfibrous scaffold, loaded with vitamin C (VitC), a bioactive molecule which acts as a protecting agent against UV damages and as a wound healing promoter. Fibers were fabricated via electrospinning from various zein/pectin formulations, and subsequently cross-linked in the presence of Ca2+ to confer them a hydrogel-like behavior, which we exploited to tune both the drug release profile and the scaffold degradation. A comprehensive characterization of the physico-chemical properties of the zein/pectin/VitC scaffolds, either pristine or cross-linked, has been carried out, together with the bioactivity assessment with two representative skin cell populations (human dermal fibroblast cells and skin keratinocytes, HaCaT cells). Interestingly, col-1a gene expression of dermal fibroblasts increased after 3 days of growth in the presence of the microfiber extraction media, indicating that the released VitC was able to stimulate collagen mRNA production overtime. Antioxidant activity was analyzed on HaCaT cells via DCFH-DA assay, highlighting a fluorescence intensity decrease proportional to the amount of loaded VitC (down to 50 and 30%), confirming the protective effect of the matrices against oxidative stress. Finally, the most performing samples were selected for the in vivo test on a skin UVB-burn mouse model, where our constructs demonstrated to significantly reduce the inflammatory cytokines expression in the injured area (50% lower than the control), thus constituting a promising, environmentally sustainable alternative to skin patches.
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Quemaduras , Animales , Humanos , Masculino , Ratones , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Ácido Ascórbico/metabolismo , Materiales Biocompatibles , Quemaduras/tratamiento farmacológico , Línea Celular , Hidrogeles , Queratinocitos , Ratones Endogámicos C57BL , Cicatrización de Heridas , Zeína/química , Zea mays/químicaRESUMEN
CDC42 GTPases (RHOJ, CDC42, and RHOQ) are overexpressed in multiple tumor types and activate pathways critical for tumor growth, angiogenesis, and metastasis. Recently, we reported the discovery of a novel lead compound, ARN22089, which blocks the interaction of CDC42 GTPases with specific downstream effectors. ARN22089 blocks tumor growth in BRAF mutant mouse melanoma models and patient-derived xenografts (PDXs) in vivo. ARN22089 also inhibits tumor angiogenesis in three-dimensional vascularized microtumor models in vitro. Notably, ARN22089 belongs to a novel class of trisubstituted pyrimidines. Based on these results, we describe an extensive structure-activity relationship of â¼30 compounds centered on ARN22089. We discovered and optimized two novel inhibitors (27, ARN25062, and 28, ARN24928), which are optimal back-up/follow-up leads with favorable drug-like properties and in vivo efficacy in PDX tumors. These findings further demonstrate the potential of this class of CDC42/RHOJ inhibitors for cancer treatment, with lead candidates ready for advanced preclinical studies.
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Neoplasias , Proteínas de Unión al GTP rho , Animales , Humanos , Ratones , Línea Celular Tumoral , Neovascularización Patológica , Quinasas p21 Activadas/metabolismo , Unión ProteicaRESUMEN
Skin burns are debilitating injuries with significant morbidity and mortality associated with infections and sepsis, particularly in immunocompromised patients. In this context, nanotechnology can provide pioneering approaches for the topical treatment of burnt skin. Herein, the significant recovery of radiation-damaged skin by exploiting copper ultrasmall-in-nano architectures (CuNAs) dispersed in a home-made cosmetic cream is described and compared to other noble metals (such as gold). Owing to their peculiar design and components, CuNAs elicit a substantial recovery from burned skin in in vivo models after one topical application, and a significant anti-inflammatory effect is highlighted by reducing cytokine expression. The treatment exhibited neither significant toxicity nor the alteration of copper metabolism in the target organs because of the CuNA biocompatibility. This study may open new horizons in the treatment of radiation dermatitis and skin burns caused by other external events.
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Biodegradable stent coatings have shown great potential in terms of delivering drugs to a damaged vessel wall, and their release profiles are key elements governing the overall performance of drug-eluting stents (DESs). However, release and degradation kinetics are usually not tested under simulated physiological conditions or in dynamic environments, both essential aspects in the design of novel DESs. To bridge this gap, fused silica-based microfluidic systems, with either round or square channel cross-sections, were designed to mimic the microenvironment of a stented vessel. In particular, we fabricated and characterized microfluidic chips based on customizable channels, which were spray-coated with a naturally-derived, rutin-loaded zein solution, to perform a comprehensive study under flow conditions. Dynamic assays after 6 hours showed how the degradation of the zein matrix was affected by the cross-sectional conformation (â¼69% vs. â¼61%, square and round channel, respectively) and the simulated blood fluid components (â¼55%, round channel with a more viscous solution). The released amount of rutin was â¼81% vs. â¼77% and â¼78% vs. â¼74% from the square and round channels, using the less and more viscous blood-simulated fluids, respectively. Fitting the drug release data to Korsmeyer-Peppas and first-order mathematical models provided further insight into the mechanism of rutin release and coating behavior under flowing conditions. More importantly, whole blood tests with our newly developed microfluidic platforms confirmed the hemocompatibility of our zein-based coating. In detail, in-flow and static studies on the blood cell behavior showed a significant reduction of platelet adhesion (â¼73%) and activation (â¼93%) compared to the stainless-steel substrate, confirming the benefits of using such naturally-derived coatings to avoid clogging. Overall, our microfluidic designs can provide a key practical tool for assessing polymer degradation and drug release from degradable matrices under flowing conditions, thus aiding future studies on the development of hemocompatible, controlled-release coatings for DESs.
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Stents Liberadores de Fármacos , Zeína , Microfluídica , Estudios Transversales , Polímeros/química , Materiales Biocompatibles Revestidos/químicaRESUMEN
The intranasal administration of drugs allows an effective and noninvasive therapeutic action on the respiratory tract. In an era of rapidly increasing antimicrobial resistance, new approaches to the treatment of communicable diseases, especially lung infections, are urgently needed. Metal nanoparticles are recognized as a potential last-line defense, but limited data on the biosafety and nano/biointeractions preclude their use. Here, we quantitatively and qualitatively assess the fate and the potential risks associated with the exposure to a silver nanomaterial model (i.e., silver ultrasmall-in-nano architectures, AgNAs) after a single dose instillation. Our results highlight that the biodistribution profile and the nano/biointeractions are critically influenced by both the design of the nanomaterial and the chemical nature of the metal. Overall, our data suggest that the instillation of rationally engineered nanomaterials might be exploited to develop future treatments for (non)communicable diseases of the respiratory tract.
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Nanopartículas del Metal , Nanoestructuras , Nanopartículas del Metal/uso terapéutico , Plata , Distribución TisularRESUMEN
Prion diseases are a group of neurodegenerative disorders characterized by the accumulation of misfolded prion protein (called PrPSc). Although conversion of the cellular prion protein (PrPC) to PrPSc is still not completely understood, most of the therapies developed until now are based on blocking this process. Here, we propose a new drug strategy aimed at clearing prions without any direct interaction with neither PrPC nor PrPSc. Starting from the recent discovery of SERPINA3/SerpinA3n upregulation during prion diseases, we have identified a small molecule, named compound 5 (ARN1468), inhibiting the function of these serpins and effectively reducing prion load in chronically infected cells. Although the low bioavailability of this compound does not allow in vivo studies in prion-infected mice, our strategy emerges as a novel and effective approach to the treatment of prion disease.
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Enfermedades por Prión , Priones , Animales , Ratones , Enfermedades por Prión/tratamiento farmacológico , Enfermedades por Prión/metabolismo , Proteínas Priónicas/metabolismo , Priones/metabolismoRESUMEN
Malva sylvestris (MS) is a medicinal herb known worldwide for its beneficial effects due to the several active molecules present in its leaves and flowers. These compounds have shown antioxidant and anti-inflammatory properties and thus can be helpful in treatments of burns and chronic wounds, characterized mainly by high levels of free radicals and impairments of the inflammatory response. In this work, we propose bilayer films as wound dressings, based on poly(vinylpyrrolidone) (PVP) and sodium alginate loaded with M. sylvestris extracts from leaves and flowers and fabricated by combining solvent-casting and rod-coating methods. The top layer is produced in two different PVP/alginate ratios and loaded with the MS flowers' extract, while the bottom layer is composed of PVP and MS leaves' extract. The bilayers were characterized morphologically, chemically, and mechanically, while they showed superior self-adhesive properties on human skin compared to a commercial skin patch. The materials showed antioxidant activity, release of the bioactive compounds, and water uptake property. Moreover, the anthocyanin content of the flower extract provided the films with the ability to change color when immersed in buffers of different pH levels. In vitro tests using primary keratinocytes demonstrated the biocompatibility of the MS bilayer materials and their capacity to enhance the proliferation of the cells in a wound scratch model. Finally, the best performing MS bilayer sample with a PVP/alginate ratio of 70:30 was evaluated in mice models, showing suitable resorption properties and the capacity to reduce the level of inflammatory mediators in UVB-induced burns when applied to an open wound. These outcomes suggest that the fabricated bilayer films loaded with M. sylvestris extracts are promising formulations as active and multifunctional dressings for treating skin disorders.
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Quemaduras , Malva , Adhesivos , Alginatos , Animales , Antioxidantes/farmacología , Vendajes , Malva/química , Ratones , Extractos Vegetales/farmacología , Cementos de ResinaRESUMEN
CDC42 family GTPases (RHOJ, RHOQ, CDC42) are upregulated but rarely mutated in cancer and control both the ability of tumor cells to invade surrounding tissues and the ability of endothelial cells to vascularize tumors. Here, we use computer-aided drug design to discover a chemical entity (ARN22089) that has broad activity against a panel of cancer cell lines, inhibits S6 phosphorylation and MAPK activation, activates pro-inflammatory and apoptotic signaling, and blocks tumor growth and angiogenesis in 3D vascularized microtumor models (VMT) in vitro. Additionally, ARN22089 has a favorable pharmacokinetic profile and can inhibit the growth of BRAF mutant mouse melanomas and patient-derived xenografts in vivo. ARN22089 selectively blocks CDC42 effector interactions without affecting the binding between closely related GTPases and their downstream effectors. Taken together, we identify a class of therapeutic agents that influence tumor growth by modulating CDC42 signaling in both the tumor cell and its microenvironment.
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Células Endoteliales , Neoplasias , Animales , Células Endoteliales/metabolismo , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Neovascularización Patológica , Transducción de Señal , Microambiente Tumoral , Proteína de Unión al GTP cdc42/metabolismo , Proteínas de Unión al GTP rho/metabolismoRESUMEN
The management of acute and chronic wounds is still a socioeconomic burden for society due to the lack of suitable tools capable of supporting all the healing phases. The exponential spread of diabetes worldwide and the consequent increase of complicated diabetic ulcers require further efforts to develop scalable, low-cost, and easy-to-use treatments for tackling this emergency. Recently, we explored the fabrication of a polyvinylpyrrolidone/hyaluronic acid-based bilayer wound dressing, characterizing its physicochemical features and detailing its excellent antimicrobial activity. Here, we further demonstrate its biocompatibility on fibroblasts, keratinocytes, and red blood cells. The bilayer shows anti-inflammatory properties, statistically reducing the level of IL-6, IL-1ß, and TNF-α, and a capacity to accelerate wound healing in vitro and in healthy and diabetic mice models compared to untreated mice. The outcomes suggest that this bilayer material can be an effective tool for managing different skin injuries.
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Inhibition of intracellular N-acylethanolamine-hydrolyzing acid amidase (NAAA) activity is a promising approach to manage the inflammatory response under disabling conditions. In fact, NAAA inhibition preserves endogenous palmitoylethanolamide (PEA) from degradation, thus increasing and prolonging its anti-inflammatory and analgesic efficacy at the inflamed site. In the present work, we report the identification of a potent, systemically available, novel class of NAAA inhibitors, featuring a pyrazole azabicyclo[3.2.1]octane structural core. After an initial screening campaign, a careful structure-activity relationship study led to the discovery of endo-ethoxymethyl-pyrazinyloxy-8-azabicyclo[3.2.1]octane-pyrazole sulfonamide 50 (ARN19689), which was found to inhibit human NAAA in the low nanomolar range (IC50 = 0.042 µM) with a non-covalent mechanism of action. In light of its favorable biochemical, in vitro and in vivo drug-like profile, sulfonamide 50 could be regarded as a promising pharmacological tool to be further investigated in the field of inflammatory conditions.
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Amidohidrolasas/antagonistas & inhibidores , Antiinflamatorios/farmacología , Inhibidores Enzimáticos/farmacología , Pirazoles/farmacología , Tropanos/farmacología , Amidohidrolasas/metabolismo , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacocinética , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacocinética , Humanos , Masculino , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Pirazoles/síntesis química , Pirazoles/metabolismo , Pirazoles/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tropanos/síntesis química , Tropanos/metabolismo , Tropanos/farmacocinéticaRESUMEN
Alterations of skin homeostasis are widely diffused in our everyday life both due to accidental injuries, such as wounds and burns, and physiological conditions, such as late-stage diabetes, dermatitis, or psoriasis. These events are locally characterized by an intense inflammatory response, a high generation of harmful free radicals, or an impairment in the immune response regulation, which can profoundly change the skin tissue' repair process, vulnerability, and functionality. Moreover, diabetes diffusion, antibiotic resistance, and abuse of aggressive soaps and disinfectants following the COVID-19 emergency could be causes for the future spreading of skin disorders. In the last years, hydroxycinnamic acids and derivatives have been investigated and applied in several research fields for their anti-oxidant, anti-inflammatory, and anti-bacterial activities. First, in this study, we give an overview of these natural molecules' current source and applications. Afterwards, we review their potential role as valid alternatives to the current therapies, supporting the management and rebalancing of skin disorders and diseases at different levels. Also, we will introduce the recent advances in the design of biomaterials loaded with these phenolic compounds, specifically suitable for skin disorders treatments. Lastly, we will suggest future perspectives for introducing hydroxycinnamic acids and derivatives in treating skin disorders.