The synthesis and in vitro and in vivo evaluation of a new series of 7-(phenylpiperidinyl)-1,2,4-triazolo4,3-apyridines, which were conveniently radiolabeled with carbon-11, as potential positron ...emission tomography (PET) radiotracers for in vivo imaging of the allosteric binding site of the metabotropic glutamate (mGlu) receptor subtype 2 are described. The synthesized compounds proved to be potent and selective positive allosteric modulators (PAMs) of the mGlu receptor 2 (mGluR2) in a 35SGTPγS binding assay and were able to displace an mGluR2 PAM radioligand, which we had previously developed, with IC50 values in the low nanomolar range. The most promising candidates were radiolabeled and subjected to biodistribution studies and radiometabolite analysis in rats. Preliminary small-animal PET (μPET) studies in rats indicated that 11C20f binds specifically and reversibly to an mGluR2 allosteric site, strongly suggesting that it is a promising candidate for PET imaging of mGluR2 in the brain.
1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pK a while optimizing ...interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aβ levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer’s disease.
Positive allosteric modulators of the metabotropic glutamate 2 receptor have generated great interest in the past decade. There is mounting evidence of their potential as therapeutic agents in the ...treatment of multiple central nervous system disorders. We have previously reported substantial efforts leading to potent and selective mGlu2 PAMs. However, finding compounds with the optimal combination of in vitro potency and good druglike properties has remained elusive, in part because of the hydrophobic nature of the allosteric binding site. Herein, we report on the lead optimization process to overcome the poor solubility inherent to the advanced lead 6. Initial prototypes already showed significant improvements in solubility while retaining good functional activity but displayed new liabilities associated with metabolism and hERG inhibition. Subsequent subtle modifications efficiently addressed those issues leading to the identification of compound 27 (JNJ-46356479). This new lead represents a more balanced profile that offers a significant improvement on the druglike attributes compared to previously reported leads.
Poly(3,4-ethylenedioxythiophene):poly (styrene sulfonate) (PEDOT:PSS) plays a relevant role in the device performance as hole extraction layer (HTL) of inverted perovskite solar cells. Here, we show ...a simple low-temperature spin coating method for obtaining homogenous graphene-doped thin films of PEDOT:PSS with improved electrical conductivity without decreasing optical transmittance. Moreover, the crystallinity and stability in ambient conditions of the perovskite grown on it are enhanced. The hydrophobic character of graphene probably blocks undesirable reactions hampering degradation. By impedance spectroscopy it is demonstrated better charge extraction and reduction of recombination mechanisms at the doped-HTL/perovskite interface, resulting in improved photovoltaic parameters of the solar cell and greater stability at room operation conditions thus providing a simple and cost-effective method of preparing solar cells based on hybrid perovskites.
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•Addition of graphene platelets into PEDOT:PSS layers improves up to 10 times its conductivity, maintaining the transmittance.•MAPbI3 film grown on graphene-doped PEDOT:PSS exhibits large crystallite size and lower PbI2 content, leading high stability.•Inverted solar cells based on graphene-doped PEDOT:PSS show better photovoltaic parameters by increasing charge extraction.
We report the synthesis and biological evaluation of a series of 7-aryl-1,2,4-triazolo4,3-apyridines with mGlu2 positive allosteric modulator (PAM) activity and affinity. Besides traditional in ...vitro parameters of potency and affinity, kinetic parameters k on, k off and residence time (RT) were determined. The PAMs showed various kinetic profiles; k on values ranged over 2 orders of magnitude, whereas RT values were within a 10-fold range. Association rate constant k on was linearly correlated to affinity. Evaluation of a short, medium, and long RT compound in a label-free assay indicated a correlation between RT and functional effect. The effects of long RT compound 9 on sleep–wake states indicated long RT was translated into sustained inhibition of rapid eye movement (REM) in vivo. These results show that affinity-only driven selection would have resulted in mGlu2 PAMs with high values for k on but not necessarily optimized RT, which is key to predicting optimal efficacy in vivo.
The poor photostability under ambient conditions of hybrid halide perovskites has hindered their recently explored promising nonlinear optical properties. Here, we show how Bi3+ can partially ...substitute Pb2+ homogeneously in the commonly studied MAPbI3, improving both environmental stability and photostability under high laser irradiation. Bi content around 2 atom % produces thin films where the nonlinear refractive (n 2) and absorptive coefficients (β), which modify the refractive index (Δn) of the material with light fluence (I), increase up to factors of 4 and 3.5, respectively, compared to undoped MAPbI3. Higher doping inhibits the nonlinear parameters; however, the samples show higher fluence damage thresholds. Thus, these results provide a road map on how MAPbI3 can be engineered for practical cost-effective nonlinear applications by means of Bi doping, including optical limiting devices and multiple-harmonic generation into optoelectronics devices.
Tb-doped TiO2 hollow spheres (HSs) in the range 0.0–2.0 at.% have been synthesized by the first time to the best of our knowledge. The HSs are compared with nanoparticles (NPs) to evaluate the impact ...of morphology on their physicochemical and photoluminescence (PL) behavior upon increasing calcination temperature. After calcination at 550 °C, the particles are anatase with a primary average size of 10.0 ± 0.2 nm for the NPs and 12.0 ± 0.2 nm for those that form the micron sized hollow spheres of 1.8 ± 0.2 μm diameter and ca. 64 nm shell thickness. The temperature of the anatase–rutile transition is found to be strongly dependent on the presence of Tb as well as on morphology. Contrarily to the usual stabilization of anatase when doping with trivalent rare-earth ions, the transition temperature is reduced when doping with Tb. The rutile phase is further favored for the HSs compared to the NPs probably related to the low density of the HSs and/or a more efficient packing density and/or a bigger crystal size of the nanoparticles that form those spheres with respect to the packing and the size of the NPs and/or the crystal size of the nanoparticles of the HSs with respect to the size of the NPs. Only a slight unit-cell volume increase for the anatase structure is observed upon Tb doping, in both the NPs and in the HSs, contrary to the expected increment due to the larger ionic radius of Tb3+ compared to Ti4+. In addition, the intensity of the characteristic f-f Tb3+ emission bands is extremely weak both in the anatase and rutile phases. The transition is accompanied with the emergence of an infrared emission band centered at 810 nm related to the formation of defects during the structural transformation providing deep levels in the gap that partly quench the f-f emissions in the rutile phase. The results are consistent with the presence of Tb in both +3 and +4 valence states. XPS measurements confirmed the presence of Tb3+ as well as of Tb4+ in both HSs and NPs. The large fraction of Tb4+ present in the samples originates the weak f-f emission intensity, an only slight increase of the cell parameters and the destabilization of the anatase phase.
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•Tb-doped TiO2 hollow spheres (HSs) have been synthesized by the first time.•The impact of Tb4+ and morphology on thermal evolution and photoluminescence properties are evaluated.•The temperature of the anatase–rutile transition is found to be strongly dependent on Tb as well as on morphology.•The transition is accompanied with emergence of deep levels that partly quench the f-f emissions.•The intensity of the f-f Tb3+ bands is consistent with the presence of Tb3+ and Tb4+.
Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. However, lower glycolysis is compromised in human clear cell renal cell carcinomas, in which HIF1α ...acts as a tumor suppressor by inhibiting cell-autonomous proliferation. Here, we find that, unexpectedly, HIF1α suppresses lower glycolysis after the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step, leading to reduced lactate secretion in different tumor cell types when cells encounter a limited pyruvate supply such as that typically found in the tumor microenvironment in vivo. This is because HIF1α-dependent attenuation of mitochondrial oxygen consumption increases the NADH/NAD+ ratio that suppresses the activity of the NADH-sensitive GAPDH glycolytic enzyme. This is manifested when pyruvate supply is limited, since pyruvate acts as an electron acceptor that prevents the increment of the NADH/NAD+ ratio. Furthermore, this anti-glycolytic function provides a molecular basis to explain how HIF1α can suppress tumor cell proliferation by increasing the NADH/NAD+ ratio.
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•HIF1α suppresses lower glycolysis when pyruvate supply is limited•Insufficient pyruvate facilitates HIF1α-dependent elevation of NADH/NAD+ ratio•Inhibition of NADH/NAD+ elevation restores lower glycolysis upon HIF1α activation•HIF1α-dependent increase in NADH/NAD+ ratio reduces cell proliferation
In this article, Urrutia et al. explain the metabolic pattern of ccRCC tumors characterized by the suppression of lower glycolysis and constitutive HIF1α activation. Urrutia et al. show that HIF1α elevates the NADH/NAD+ ratio, which attenuates lower glycolysis when pyruvate supply is limited, as occurs in the solid tumor microenvironment.
Advanced leads of an imidazopyridine series of positive allosteric modulators of the metabotropic glutamate 2 (mGlu2) receptor are reported. The optimization of in vitro ADMET and in vivo ...pharmacokinetic properties led to the identification of 27o. With good potency and selectivity for the mGlu2 receptor, 27o affected sleep–wake architecture in rats after oral treatment, which we have previously shown to be indicative of mGlu2 receptor-mediated central activity.
After gaining experience conducting both auto and allografts in persons with hematological diseases in the HSCT programs in Puebla and Monterrey, México, this study outlines subsequent program ...autografting patients with autoimmune conditions. The first transplant in multiple sclerosis was conducted in Puebla on July 5, 2006. From 2015 we increased activity autografting persons with autoimmune conditions in the two campuses of the HSCT-México program: Puebla and Monterrey. By December 6, 2020, patient number 1,000 in the program was autografted. In our experience, a significant reduction in the expanded disability status scale score was achieved in all of the three phenotypes of the disease (from a median of 5.1 to 4.5 points), whereas the response rate (defined as a decrease of at least 0.5 of EDSS score regardless of baseline EDSS, or unchanged EDSS) was 83, 78, and 73% after 12 months in the relapsing-remitting, primary-progressive and secondary-progressive forms of multiple sclerosis, respectively. In addition to analyzing the viability, safety, and efficacy of our method, this study contributes new knowledge to the field of both stem cell transplantation and multiple sclerosis.
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