Day: December 21, 2022

Ashworth, Ian W. published the artcileProcess Development of a Suzuki Reaction Used in the Manufacture of Lanabecestat, HPLC of Formula: 917471-30-8, the main research area is lanabecestat preparation; Suzuki coupling diethanolamine alkynylpyridinylboronate bromodispirocyclohexaneindaneimidazole key step; hydrolysis kinetics diethanolamine alkynylpyridinylboronate; effect diethanolamine removal palladium lanabecestat.

A process for preparation of the potential anti-Alzheimer’s agent lanabecestat was developed by coupling of an alkynylpyridinylboronic acid diethanolamine ester with a bromodispirocyclohexaneindaneimidazole in the presence of Pd(AmPhos)2Cl2 and K3PO4 in EtOH/H2O; the new process reduced the need for solvent changes and difficult isolation steps and decreased the amount of palladium detected in the final product without the use of solid-phase extractants. The kinetics of hydrolysis of the diethanolamine boronate and the free boronic acid was determined; diethanolamine generated in the hydrolysis decreased the rate of coupling but likely improved the purge of palladium from the product.

Organic Process Research & Development published new progress about Hydrolysis. 917471-30-8 belongs to class pyridine-derivatives, name is (5-(Prop-1-yn-1-yl)pyridin-3-yl)boronic acid, and the molecular formula is C8H8BNO2, HPLC of Formula: 917471-30-8.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Dantonio, Alyssa L. published the artcileIntersystem extrapolation factors are substrate-dependent for CYP3A4: impact on cytochrome P450 reaction phenotyping, Recommanded Product: 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, the main research area is intersystem extrapolation factor CYP3A4 reaction phenotyping pharmacokinetics.

The use of intersystem extrapolation factors (ISEF) is required for the quant. scaling of drug metabolism data generated in individually expressed cytochrome P 450 (CYP) enzymes when estimating fractional contribution (fm) to metabolism by P 450 enzymes in vivo. For successful prediction of fm, ISEF values must be universal across all substrates for any individual enzyme. In this study, ISEF values were generated for ten CYP3A4 selective substrates using a common source of recombinant heterologously expressed CYP3A4 (rCYP) and a pool of human liver microsomes. The resulting ISEF values for CYP3A4 were substrate-dependent and ranged 8-fold, with the highest value generated from intrinsic clearance of midazolam depletion (0.36) and the lowest from quinidine depletion (0.044). Application of these ISEF values for estimation of the fractional contribution of CYP3A4 and CYP2C19 to omeprazole clearance yielded values that ranged from 0.21-0.63 and 0.37-0.79, resp., as compared with back-extrapolated in vivo fm values of 0.27 (CYP3A4) and 0.85 (CYP2C19) from clin. pharmacokinetic data. For risperidone, estimated fm values for CYP3A4 and CYP2D6 ranged from 0.87-0.98 and 0.02-0.13, resp., as compared with in vivo values of 0.36 (CYP3A4) and 0.63-0.88 (CYP2D6), showing that the importance of CYP3A4 was overestimated, and the importance of CYP2D6 underestimated. Overall, these findings suggest that ISEF values for CYP3A4 can vary with the marker substrate used to derive them, thereby reducing the effectiveness of the approach of using metabolism data from rCYP3A4 with ISEF values for the prediction of fraction metabolized values in vivo.

Drug Metabolism & Disposition published new progress about Hepatocyte. 72509-76-3 belongs to class pyridine-derivatives, name is 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C18H19Cl2NO4, Recommanded Product: 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Brinkmann, Joscha published the artcileIn-Silico Screening of Lipid-Based Drug Delivery Systems, Application In Synthesis of 72509-76-3, the main research area is lipid based drug delivery system screening formulation; PC-SAFT; lipid-based formulations; solubility; thermodynamic modeling.

This work proposes an in-silico screening method for identifying promising formulation candidates in complex lipid-based drug delivery systems (LBDDS). The approach is based on a min. amount of exptl. data for API solubilites in single excipients. Intermol. interactions between APIs and excipients as well as between different excipients were accounted for by the Perturbed-Chain Statistical Associating Fluid Theory. The approach was applied to the in-silico screening of lipid-based formulations for ten model APIs (fenofibrate, ibuprofen, praziquantel, carbamazepine, cinnarizine, felodipine, naproxen, indomethacin, griseofulvin and glibenclamide) in mixtures of up to three out of nine excipients (tricaprylin, Capmul MCM, caprylic acid, Capryol 90, Lauroglycol FCC, Kolliphor TPGS, polyethylene glycol, carbitol and ethanol). For eight out of the ten investigated model APIs, the solubilities in the final formulations could be enhanced by up to 100 times compared to the solubility in pure tricaprylin. Fenofibrate, ibuprofen, praziquantel, carbamazepine are recommended as type I formulations, whereas cinnarizine and felodipine showed a distinctive solubility gain in type II formulations. Increased solubility was found for naproxen and indomethacin in type IIIb and type IV formulations. The solubility of griseofulvin and glibenclamide could be slightly enhanced in type IIIb formulations. The exptl. validation agreed very well with the screening results. The API solubility individually depends on the choice of excipients. The proposed in-silico-screening approach allows formulators to quickly determine most-appropriate types of lipid-based formulations for a given API with low exptl. effort.

Pharmaceutical Research published new progress about Cosolvents. 72509-76-3 belongs to class pyridine-derivatives, name is 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C18H19Cl2NO4, Application In Synthesis of 72509-76-3.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Gui, Yue published the artcilePolymorphic selectivity in crystal nucleation, Computed Properties of 21829-25-4, the main research area is polymorphic selectivity crystal nucleation glass forming liquid.

Crystal nucleation rates were measured in the supercooled melts of 2 richly polymorphic glass-forming liquids: 5-Me-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY) and nifedipine (NIF). ROY is known for its crystals of red, orange, and yellow colors and many polymorphs of solved structures. Of the many polymorphs, ON (orange needles) nucleates the fastest with the runner up (Y04) trailing by a factor of 103 when compared under the same mobility-limited condition, while the other unobsd. polymorphs are slower yet by â‰? orders of magnitude. Of the 6 polymorphs of NIF, γ’ nucleates the fastest, β’ is slower by a factor of 10, and the rest are slower yet by â‰? decades. In both systems, the faster-nucleating polymorphs are not built from the lowest-energy conformers, while they tend to have higher energies and lower densities and thus greater similarity to the liquid phase by these measures. The temperature ranges of this study covered the glass transition temperature Tg of each system, and no evidence that the nucleation rate is sensitive to the passage of Tg were found. At the lowest temperatures studied, the rates of nucleation and growth are proportional to each other, indicating that a similar kinetic barrier controls both processes. The classical nucleation theory provides an accurate description of the observed nucleation rates if the crystal growth rate is used to describe the kinetic barrier for nucleation. The quant. rates of both nucleation and growth for the competing polymorphs enable prediction of the overall rate of crystallization and its polymorphic outcome. (c) 2022 American Institute of Physics.

Journal of Chemical Physics published new progress about Conformers. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Computed Properties of 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Held, Katharina published the artcilePharmacological properties of TRPM3 isoforms are determined by the length of the pore loop, Computed Properties of 21829-25-4, the main research area is trpm3 pore loop length pharmacol property; Splice variants TRP channels; TRPM3; nociception.

Background and Purpose : Transient receptor potential melastatin 3 (TRPM3) is a non-selective cation channel that plays a pivotal role in the peripheral nervous system as a transducer of painful heat signals. Alternative splicing gives rise to several TRPM3 variants. The functional consequences of these splice isoforms are poorly understood. Here, the pharmacol. properties of TRPM3 variants arising from alternative splicing in the pore-forming region were compared. Exptl. Approach : Calcium microfluorimetry and patch clamp recordings were used to compare the properties of heterologously expressed TRPM3α1 (long pore variant) and TRPM3α2-α6 (short pore variants). Furthermore, site-directed mutagenesis was done to investigate the influence of the length of the pore loop on the channel function. Key Results : All short pore loop TRPM3α variants (TRPM3α2-α6) were activated by the neurosteroid pregnenolone sulfate (PS) and by nifedipine, whereas the long pore loop variant TRPM3α1 was insensitive to either compound In contrast, TRPM3α1 was robustly activated by clotrimazole, a compound that does not directly activate the short pore variants but potentiates their responses to PS. Clotrimazole-activated TRPM3α1 currents were largely insensitive to established TRPM3α2 antagonists and were only partially inhibited upon activation of the μ opioid receptor. Finally, by creating a set of mutant channels with pore loops of intermediate length, we showed that the length of the pore loop dictates differential channel activation by PS and clotrimazole. Conclusion and Implications : Alternative splicing in the pore-forming region of TRPM3 defines the channel’s pharmacol. properties, which depend critically on the length of the pore-forming loop.

British Journal of Pharmacology published new progress about Cerebellum. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Computed Properties of 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Lin, Yi-Sian published the artcileGWAS Meta-Analysis Reveals Shared Genes and Biological Pathways between Major Depressive Disorder and Insomnia, SDS of cas: 72509-76-3, the main research area is major depressive disorder insomnia gene biol pathway metaanalysis; GWAS; MDD; STRING; comorbidity; eQTL; gene network; insomnia; meta-analysis.

Major depressive disorder (MDD) is one of the most prevalent and disabling mental disorders worldwide. Among the symptoms of MDD, sleep disturbance such as insomnia is prominent, and the first reason patients may seek professional help. However, the underlying pathophysiol. of this comorbidity is still elusive. Recently, genome-wide association studies (GWAS) have begun to unveil the genetic background of several psychiatric disorders, including MDD and insomnia. Identifying the shared genomic risk loci between comorbid psychiatric disorders could be a valuable strategy to understanding their comorbidity. This study seeks to identify the shared genes and biol. pathways between MDD and insomnia based on their shared genetic variants. First, we performed a meta-anal. based on the GWAS summary statistics of MDD and insomnia obtained from Psychiatric Genomics Consortium and UK Biobank, resp. Next, we associated shared genetic variants to genes using two gene mapping strategies: (a) positional mapping based on genomic proximity and (b) expression quant. trait loci (eQTL) mapping based on gene expression linkage across multiple tissues. As a result, a total of 719 shared genes were identified. Over half (51%) of them are protein-coding genes. Functional enrichment anal. shows that the most enriched biol. pathways are related to epigenetic modification, sensory perception, and immunol. signatures. We also identified druggable targets using a network approach. Together, these results may provide insights into understanding the genetic predisposition and underlying biol. pathways of comorbid MDD and insomnia symptoms.

Genes published new progress about Cerebellum. 72509-76-3 belongs to class pyridine-derivatives, name is 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C18H19Cl2NO4, SDS of cas: 72509-76-3.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Ulivieri, Alessandra published the artcileThyroid hormones regulate cardiac repolarization and QT-interval related gene expression in hiPSC cardiomyocytes, Formula: C17H18N2O6, the main research area is thyroid hormone induced pluripotent stem cardiomyocyte cardiac dysfunction.

Prolongation of cardiac repolarization (QT interval) represents a dangerous and potentially life-threatening elec. event affecting the heart. Thyroid hormones (THs) are critical for cardiac development and heart function. However, little is known about THs influence on ventricular repolarization and controversial effects on QT prolongation are reported. Human iPSC-derived cardiomyocytes (hiPSC-CMs) and multielectrode array (MEA) systems were used to investigate the influence of 3,3′,5-triiodo-L-Thyronine (T3) and 3,3′,5,5′-tetraiodo-L-Thyronine (T4) on corrected Field Potential Duration (FPDc), the in vitro analog of QT interval, and on local extracellular Action Potential Duration (APD). Treatment with high THs doses induces a significant prolongation of both FPDc and APD, with the strongest increase reached after 24 h exposure. Preincubation with reverse T3 (rT3), a specific antagonist for nuclear TH receptor binding, significantly reduces T3 effects on FPDc, suggesting a TRs-mediated transcriptional mechanism. RNA-seq anal. showed significant deregulation in genes involved in cardiac repolarization pathways, including several QT-interval related genes. In conclusion, long-time administration of high THs doses induces FPDc prolongation in hiPSC-CMs probably through the modulation of genes linked to QT-interval regulation. These results open the way to investigate new potential diagnostic biomarkers and specific targeted therapies for cardiac repolarization dysfunctions.

Scientific Reports published new progress about Biomarkers. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Formula: C17H18N2O6.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Korkka, Iina published the artcileFunctional Voltage-Gated Calcium Channels Are Present in Human Embryonic Stem Cell-Derived Retinal Pigment Epithelium, Quality Control of 21829-25-4, the main research area is calcium channel embryonic stem cell retinal pigment epithelium disease; Patch-clamp; Phagocytosis; Retinal pigment epithelium; Stem cells; Vascular endothelial growth factor; Voltage-gated Ca2+ channels.

Retinal pigment epithelium (RPE) performs important functions for the maintenance of photoreceptors and vision. Malfunctions within the RPE are implicated in several retinal diseases for which transplantations of stem cell-derived RPE are promising treatment options. Their success, however, is largely dependent on the functionality of the transplanted cells. This requires correct cellular physiol., which is highly influenced by the various ion channels of RPE, including voltage-gated Ca2+ (CaV) channels. This study investigated the localization and functionality of CaV channels in human embryonic stem cell (hESC)-derived RPE. Whole-cell patch-clamp recordings from these cells revealed slowly inactivating L-type currents comparable to freshly isolated mouse RPE. Some hESC-RPE cells also carried fast transient T-type resembling currents. These findings were confirmed by immunostainings from both hESC- and mouse RPE that showed the presence of the L-type Ca2+ channels CaV1.2 and CaV1.3 as well as the T-type Ca2+ channels CaV3.1 and CaV3.2. The localization of the major subtype, CaV1.3, changed during hESC-RPE maturation co-localizing with pericentrin to the base of the primary cilium before reaching more homogeneous membrane localization comparable to mouse RPE. Based on functional assessment, the L-type Ca2+ channels participated in the regulation of vascular endothelial growth factor secretion as well as in the phagocytosis of photoreceptor outer segments in hESC-RPE. Overall, this study demonstrates that a functional machinery of voltage-gated Ca2+ channels is present in mature hESC-RPE, which is promising for the success of transplantation therapies.

Stem Cells Translational Medicine published new progress about Biomarkers. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Quality Control of 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Langston-Cox, A. G. published the artcileSulforaphane Bioavailability and Effects on Blood Pressure in Women with Pregnancy Hypertension, Recommanded Product: Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, the main research area is sulforaphane bioavailability blood pressure pregnancy hypertension women; Antioxidant; Bioavailability; Broccoli; Preeclampsia; Sulforaphane.

Sulforaphane, an isothiocyanate found in cruciferous vegetables such as broccoli, shows promise as an adjuvant therapy for preeclampsia. To inform future clin. trials, we set out to determine the bioavailability of sulforaphane in non-pregnant and preeclamptic women. In six healthy female volunteers, we performed a crossover trial to compare the bioavailability of sulforaphane and metabolites afforded by activated and non-activated broccoli extract preparation We then undertook a dose escalation study of the activated broccoli extract in 12 women with pregnancy hypertension. In non-pregnant women, an equivalent dose of activated broccoli extract gave higher levels of sulforaphane and metabolites than a non-activated extract (p < 0.0001) and greater area under the curve (AUC) (3559 nM vs. 2172 nM, p = 0.03). Compared to non-pregnant women, in women with preeclampsia, the same dose of activated extract gave lower levels of total metabolites (p < 0.000) and AUC (3559 nM vs. 1653 nM, p = 0.007). Doubling the dose of the activated extract in women with preeclampsia doubled levels of sulforaphane and metabolites (p = 0.02) and AUC (1653 nM vs. 3333 nM, p = 0.02). In women with preeclampsia, activated broccoli extract was associated with modest decreases in diastolic blood pressure (p = 0.05) and circulating levels of sFlt-1 (p = 0.0002). A myrosinase-activated sulforaphane formulation affords better sulforaphane bioavailability than a non-activated formulation. Higher doses of sulforaphane are required to achieve likely EDs in pregnant women than in non-pregnant women. Sulforaphane may improve endothelial function and blood pressure in women with pregnancy hypertension. Reproductive Sciences published new progress about Biomarkers. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Recommanded Product: Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Farrah, Tariq E. published the artcileEndothelin Receptor Antagonism Improves Lipid Profiles and Lowers PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) in Patients With Chronic Kidney Disease, Computed Properties of 21829-25-4, the main research area is chronic kidney disease lipid PCSK9 endothelin receptor antagonism; atherosclerosis; cardiovascular disease; cholesterol; endothelins; triglycerides.

We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary anal. of a fully randomized, double-blind, 3-phase crossover study. Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 wk dosing with placebo, the selective ETA receptor antagonist, sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 wk. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 wk of ETA antagonism significantly reduced total (-11±1%) and low-d. lipoprotein-associated (-20±3%) cholesterol, lipoprotein (a) (-16±2%) and triglycerides (-20±4%); high-d. lipoprotein-associated cholesterol increased (+14±2%), P<0.05 vs. baseline for all. Addnl., ETA receptor antagonism, but neither placebo nor nifedipine, reduced circulating PCSK9 (-19±2%; P<0.001 vs. baseline; P<0.05 vs. nifedipine and placebo). These effects were independent of statin use and changes in blood pressure or proteinuria. Selective ETA antagonism improves lipid profiles in optimally-managed patients with CKD, effects that may occur through a reduction in circulating PCSK9. ETA receptor antagonism offers a potentially novel strategy to reduce cardiovascular disease risk in CKD. Hypertension published new progress about Antagonism. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Computed Properties of 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem