Stability Studies Research Articles

Apremilast Amorphous Solid Dispersions: Formulation Optimization using QbD and Comprehensive In vitro-In silico Assessment

Aim: The study aims to develop a 3rd generation amorphous solid dispersion (ASD) of Apremilast (APST) employing the Design of Experiment (DoE) methodology, followed by a thorough assessment including in silico pharmacokinetics. Background: APST, classified as a BCS-Class IV molecule due to its low solubility and permea-bility, exhibits highly variable oral bioavailability across different species. Objective: In this study, a 3rd generation ASD of APST was developed using the DoE approach. Methods: The miscibility of APST within polymers was assessed using solubility parameters and Flory Huggin equations. Phase solubility studies were conducted to identify the most suitable polymer-surfactant combination for maximizing drug solubility. The produced solid dispersions were characterized using FTIR, DSC, XRD, DVS, and SEM. Results: The combination of APST and Soluplus® in a 1:5 ratio resulted in the highest improve-ment in solubility and dissolution, with vitamin E TGPS being identified as the most efficient sur-factant. Stability studies were carried out, and findings revealed that the ASD remained stable un-der accelerated conditions for up to 3 months, suggesting its suitability for scaling up for industri-al applications. In silico predictions of the pharmacokinetics of APST following oral administra-tion of solid dispersion formulations were determined by PBBM using GastroPlus™. Conclusion: The simulation of oral absorption profiles for APST showed a significant improve-ment in both Cmax and AUC for the solid dispersion formulations compared to plain drugs. This study makes a significant contribution to the field of pharmaceutical science by addressing the formulation complexities inherent in poorly water-soluble compounds like APST.

Dodecagonal GaN Microrods: Chemical Stability of a‐, m‐, and c‐Plane Walls and Their Application to Water‐Splitting

AbstractPhotoelectrolysis of water is a sustainable option for the production of hydrogen fuel. GaN nano‐ or microstructures are considered for water‐splitting due to their general high chemical stability and high surface‐to‐volume ratio enhancing the process effectiveness. In this study GaN structures with dodecagonal microrods are used as a working electrode for the water‐splitting process. Microrods are grown using a plasma‐assisted molecular beam epitaxy process allowing tailoring of microrod height and density. Their unique property is the of presence twelve sidewalls with alternating a‐ and m‐plane orientations. This enables a simultaneous study of the chemical stability of c‐, a‐, and m‐plane walls of GaN. The water‐splitting process is performed using a 1 mol l−1 NaOH electrolyte solution. Non‐zero current measured at zero bias under illumination indicates that the process takes place. A degradation of the GaN structure is observed after a prolonged process time. In short‐term exposures, etching of microrod sidewalls is observed. Roughening of the a‐plane walls studied by transmission electron microscopy indicates that this orientation is etched with a fastest rate. The internal crystalline structure is not influenced by the etching and remains stable as shown by the X‐ray absorption spectroscopy study.

Design and Characterization of Liposomal-Based Carriers for the Encapsulation of Rosa canina Fruit Extract: In Vitro Gastrointestinal Release Behavior

The increasing demand for natural compounds as an alternative to synthetic antioxidants and conservans has led to the utilization of secondary plant metabolites in the food industry, as these bioactive compounds possess great antioxidative and antimicrobial properties without side effects on human health. Despite this, the sensitivity of plant-derived compounds is a restrictive factor in terms of their full potential. The current research aimed to characterize rosehip-fruit-extract-loaded liposomes (non-treated and UV-irradiated) in terms of their density, surface tension, viscosity, chemical composition (FTIR and HPLC analyses), and thermal behavior. In the storage stability study, the vesicle size, polydispersity index (PDI), zeta potential, conductivity, and mobility of the liposomes were monitored. FTIR analysis confirmed that the plant compounds were successfully loaded within the carrier, while no chemical reaction between the rosehip fruit extract and phospholipids was detected. The results of the HPLC analysis evidence the high potential for liposomal encapsulation to protect sensitive bioactives in the rosehip fruit extract from the degrading effect of UV irradiation. The size of the rosehip-fruit-extract-encapsulated liposomes increased on the seventh day of storage from 250 nm to 300 nm, while the zeta potential values were between −21 mV and −30 mV in the same period and further stabilized over 60 days of monitoring. In Vitro release studies in water and simulated gastrointestinal fluids showed that the presence of enzymes and bile salts (in intestinal fluid) enhanced the rosehip–polyphenol permeability from liposomes (70.3% after 6 h) compared with their release in water after 24 h and in gastric fluid after 4 h (38.9% and 41.4%, respectively). The obtained results indicate that the proliposome method was an effective method for rosehip fruit extract liposomal encapsulation and for the delivery of these plant-derived bioactives in foods.

Sensitivity and Stability Study of Test Conditions for a 1 kW Proton Exchange Membrane Fuel Cell Stack

This study investigates the impact of compression force on stack performance and the effect of testing conditions on sensitivity of stack performance. It explores the variation of assembly force on the pressure distribution at different positions in a 1 kW proton exchange membrane fuel cell stack. Polarization curves and high-frequency resistance (HFR) changes of the stack were measured under different assembly forces, and the optimal assembly force of the stack was determined using the average single-cell voltage (HFR-free). The sensitivity of testing conditions was optimized, and the optimum test parameters at different current densities were identified within the selected range. Stack stability was tested at different current densities using the optimized test conditions, and the sensitivity of test conditions was verified by the fluctuation amplitude of single cell voltage and internal impedance.

The effect of Zn2+ on the positive electrolyte for all-vanadium redox flow battery

In this work, the effects of Zn2+ on the electrochemical activity of positive electrolyte were researched by cyclic voltammetry(CV), AC impedance. The results of CV showed that the positive electrolyte containing 2 wt% Zn2+ as additive had the best electrochemical activity. Compared with the electrolyte without any additive, the electrolyte with 2 wt% Zn2+ obviously enhanced electrochemical activity and reversibility of Farady reaction. In addition, the kinetic study of the mass transfer process indicated that the diffusion coefficient obviously increased. Besides, the results of electrochemical impedance spectroscopy implied that the internal charge transfer resistance of the electrolyte electrochemical system containing Zn2+ as an additive was significantly reduced. This indicated that the charge transfer was significantly accelerated, which was beneficial to the improvement of the electrochemical activity. Moreover, the study of the electrolyte stability showed that the electrolyte containing Zn2+ had superior stability yet after 30 cycles’ scanning.

PEGylated pH-Responsive Liposomes for Enhancing the Intracellular Uptake and Cytotoxicity of Paclitaxel in MCF-7 Breast Cancer Cells.

This study aimed to develop paclitaxel (PTX)-loaded PEGylated (PEG)-pH-sensitive (SpH) liposomes to enhance drug delivery efficiency and cytotoxicity against MCF-7 breast cancer cells. PTX-loaded PEG-SpH liposomes were prepared using the thin film hydration method. ATR-FTIR compatibility studies revealed no significant interactions among liposome formulation components. TEM images confirmed spherical morphology, stability, and an ideal size range (180-200nm) for improved blood circulation. At pH 5.5, liposomes exhibited increased size and positive zeta potential, indicating pH-sensitive properties due to CHEMS response to the acidic tumor microenvironment. Conversely, at pH 7.4, liposomes showed a slightly larger size (199.25 ± 1.64nm) and a more negative zeta potential (-36.94 ± 0.32mV), suggesting successful PEG-SpH surface modification, enhancing stability, and reducing aggregation. PTX-loaded PEG-SpH liposomes demonstrated high encapsulation efficiency (84.57 ± 0.92% w/w) and drug loading capacity (4.12 ± 0.26% w/w). In-vitro drug release studies revealed accelerated first-order PTX release at pH 5.5 and a controlled zero-order release at pH 7.4. Cellular uptake studies on MCF-7 cells demonstrated enhanced PTX uptake, attributed to mPEG-PCL incorporation prolonging circulation time and CHEMS facilitating PTX release in the tumor microenvironment. Furthermore, PTX-loaded PEG-SpH liposomes exhibited significantly improved cytotoxicity with an IC50 value of 1.107µM after 72-h incubation, approximately 90% lower than plain PTX solution. Stability studies confirmed the robustness of the liposomal formulation under various storage conditions. These findings highlight the potential of PEGylated pH-responsive liposomes as effective nanocarriers for enhancing PTX therapy against breast cancer.

Heteroleptic Triazole-Bisoxazoline Iron Complexes Reveal Lability of the Iron-Carbene Bond Even Within a Chelating Scaffold.

N-Heterocyclic carbenes have proven to be excellent ligands for transition metals, with numerous applications in catalysis and beyond. However, they have also displayed lability with first row transition metals, largely due to the hard-soft mismatch of the metal-carbon bond. Chelation is often considered a suitable methodology for supporting the labile M-C bond through the introduction of a strongly coordinating donor site such as hard phenolates. Herein, we demonstrate that chelating phenolate-carbene ligands are kinetically labile in iron(II) complexes. Specifically, heteroleptic iron complexes [Fe(C^O)(N^N)] were synthesized composed of a phenolate-functionalized triazolylidene (CO) ligand and N,N-bidentate coordinating bisoxazoline ligand (N^N). Stability studies by 1H NMR spectroscopy showed that the heteroleptic complexes preferentially convert to their corresponding homoleptic complexes [Fe(C^O)2] and [Fe(N^N)2], indicating reversible decoordination of the carbene phenolate chelate from the iron center. The rate of this rearrangement is dependent on the substituents on the ligands and increases for triazolylidene wingtip groups mesityl (Mes) < di(isopropyl)aryl (DIPP) < adamantyl (Ad), with significant ligand redistribution for DIPP and Ad systems observed even at room temperature. The most stable heteroleptic complex featured mesityl wingtips on the triazole and phenyl groups as oxazoline substituents and displayed signs of ligand exchange only after 16 h at room temperature. This substitutional lability of carbene ligands even when supported by a phenolate chelating group has direct consequences when designing iron complexes for catalytic applications.

Assessment of Quality Control parameters under Accelerated Stability Conditions for Manasamitra Vatakam; A Herbo Mineral Formulation

Accelerated Stability Studies predicts the stability data and significantly explains the drug decision process. In the present study, Manasamitra Vatakam, a Herbo mineral formulation was subjected to stability conditions at 40°C ± 2°C /75%± 5% RH for 06 months. Control and stability samples were determined for parameters like Weight variation, Moisture content, Marker content determination, and Disintegration test, Dissolution study with different mediums, Friability and Hardness test. The phytomarker analysis showed decrease assay value for β-sitosterol, Vitexin, Kampferol and Withaferin. The dissolution studies were performed for the major biomarker Berberine in 0.1N HCl, pH 4.5 acetate and pH 6.8 phosphate buffer in which pH 6.8 buffer showed maximum release of 66.82% at 04 hours. The other Quality control parameters showed minimal difference under acceptance criteria. The study explains the need of stability analysis in polyherbal formulations and developed method can be used for routine analytical studies in various formulation containing berberine. Keywords: Berberine, HPLC, Manasamitra Vatakam, Quality Control, Stability.

Novel antimicrobial peptides based on Protegrin-1: In silico and in vitro assessments

The development of antibiotic resistance has caused significant health problems. Antimicrobial peptides (AMPs) are considered next-generation antibiotics. Protegrin-1 (PG-1) is a β-hairpin AMP with a membrane-binding capacity. This study used twelve PG-1 analogs with different amino acid substitutions. Coarse-grained molecular dynamics (MD) simulations were used to assess these analogs, and their physicochemical properties were computed using the Antimicrobial Peptide Database. Three AMPs, PEP-D, PEP-C, and PEP-H, were chosen and synthesized for antibacterial testing. The microbroth dilution technique and hemolytic assays evaluated the antimicrobial efficacy and cellular toxicity. The checkerboard method was used to test the combined activity of AMP and standard antibiotics. Cell membrane permeability and electron microscopy were used to evaluate the mode of action. The chemical stability of the selective AMP, PEP-D, was assessed by a validated HPLC method. PEP-D consists of 16–18 amino acid residues and has a charge of +7 and a hydrophobicity of 44 %, similar to PG-1. It can efficiently inactivate bacteria by disrupting cell membranes and significantly reducing hemolytic activity. Chemical stability studies indicated that AMP was stable at 40 °C for six months under autoclave conditions. This study could introduce the potential therapeutic application of selective AMP as an anti-infective agent.

Development of a novel intramuscular liposomal injection for advanced meloxicam delivery: Preparation, characterization, in vivo pharmacokinetics, pharmacodynamics, and pain assessment in an orthopedic pain model

Pain produces several physiological, and degenerative complications. This study aimed to formulate meloxicam (MLX) in liposomes to increase solubility and deliver MLX in a controlled manner to overcome its poor aqueous solubility and relatively short t1/2 problems. Liposomes were prepared by thin film hydration followed by ultrasonication. Tests for characterizing formulations included particle size, span, entrapment efficiency, drug loading, stability, differential scanning calorimetry (DSC), Fourier transformation infrared (FT-IR) spectroscopy, morphology, in vitro release, release kinetics mathematical modeling, and an in vivo pain model in dogs undergoing orthopedic surgeries, followed by in vivo pharmacokinetics, pharmacodynamics, and pain assessment studies in comparison to the reference standard, Mobitil®. Liposomal MLX had a particle size of around 100 nm, 82 % entrapment efficiency, and 4.62 % drug loading. Stability studies, DSC, and FT-IR spectroscopy indicated that liposomes were highly stable. The formulation showed an improved in vitro controlled release pattern and an enhanced in vivo pharmacokinetic behavior as manifested by higher t1/2 and AUC0–24 and lower Cl/F in comparison to Mobitil®. The pharmacodynamics study and pain scales demonstrated liposomal MLX managed postoperative pain better than Mobitil®. In conclusion, the incorporation of MLX in liposomes increased its solubility and stability, as well as its pain management properties.

Two-positron-bonded dihalides: Ps2XY (X,Y=F,Cl,Br).

This study explores the energetic stability and physical prop-This study explores the energetic stability and physical properties of Ps2XY complexes formed by two halide anions (X-,Y-=F-,X-,Br-), and two positrons (Ps:positron-electronpair). We combine electronic coupled cluster (CCSD(T)) calculations with positronic multicomponent renormalized partialthird-order propagator (MC-REN-PP3) calculations to effectively recover correlation energies. Analysis of potential energy curves confirms the energetic stability of these positronicmolecules, with optimized structures identified as global minima. Further investigation of electron and positron densitiesreveals stabilization owing to the formation of two-positron bonds. The global stability of the Ps2XY complexes contrastswith the metastable two-positron-bonded (PsH)2, which energetically favors the emission of Ps2. Comparative analysis of one- and two-positron dihalides indicates that addinga positron to PsXY- generally results in shorter bond distances, higher force constants, and lower dissociation energies, with exceptions due to differences in positron affinities ofPsXY- and Y-. We explore the analogy between two-positron-bonded dihalide systems Ps2XY and two-electron-bonded dialkali molecules AB, (A,B=Na,K,Rb). The bonding properties in positron dihalides and their electronic dialkali analogs displayidentical periodic trends. However,compared to their isoelectronic AB counterparts, the positron bonds in Ps2XYhave shorter bond lengths, higher force constants, and higher bond energies.

R-C-D-F machine learning method to measure for geological structures in 3D point cloud of rock tunnel face

This study introduces an innovative Roughness-CANUPO-Dip-Facet (R-C-D-F) methodology for the measurement of dip angle and direction in geological rock facets. The R-C-D-F method is distinguished by its comprehensive four-step approach, encompassing filtration through roughness analysis, CANUPO analysis, and dip angle filtration, followed by facet segmentation as the measurement step. To achieve precise and efficient results, the method specifically focuses on isolating joint embedment, achieved by systematically filtering out joint bands. This selective filtration process ensures that measurements are conducted exclusively on relevant joint embedment points. The novelty of this methodology lies in its capability to automatically eliminate joint bands while retaining the joint embedment points, facilitating precise measurements without manual intervention. Three site models were evaluated using the R-C-D-F method, alongside four different techniques for measuring dip angle and direction: plane fitting, normal vector conversion, facet segmentation, and compass measurements. The results demonstrated that all methods accurately calculated the dip angle, with an accuracy ranging from 97 % to 99.4 %. The facet segmentation method was selected as the optimal measurement tool due to its automatic nature and capacity to provide accurate results without manual intervention. Furthermore, the optimal local neighbour radius (LNR) for calculating normal vectors was determined, with findings indicating that a larger LNR value enhances accuracy but also increases computational time. A verification was conducted to estimate the dip angle used for filtering and discarding additional points representing joint rock bands, with the optimal value being 45, 30, and 45 degrees for the respective sites.The R-C-D-F method effectively detected and eliminated 100 % of joint band points while retaining 81 % of joint embedment points, and the facet segmentation method provided accurate dip angle and direction measurements for each joint embedment segment. These outcomes underscore the robustness and precision of the R-C-D-F method in geological engineering and rock stability studies.

Design and fabrication of MnCo2O4@MnCo2S4 Core@Shell nanostructured arrays decorated over the rGO sheets for high-performance asymmetric supercapacitor

In order to create reliable and effective energy storage systems, it is crucial to choose electrode materials that exhibit high stability and energy density. In this work, MnCo2S4@MnCo2O4 core@shell nanoneedle-like nanostructures (MCS@MCO/rGO) are synthesised over a rGO sheet using an innovative and easy hydrothermal technique. Electrolyte transport and sulphur incorporation during charge-discharge reactions are both made easier by the core@shell nanostructured arrays' large active surface area. With an appropriate pore size distribution centred at 13.4 nm and a high surface area of 125.4 m2g-1, the ternary electrodes composed of MCS@MCO and rGO have a rich mesoporous structure. A specific capacitance of 1346 Fg-1 at 1 Ag-1 demonstrates the exceptional performance of the MCS@MCO/rGO ternary electrode. The MCS@MCO/rGO ternary electrodes show a remarkable cyclic stability of 88.9 % capacity retention over 10,000 cycles, according to the cycling stability studies. With an impressive power density of 1010 Wkg-1 and remarkable cycling stability (95.5 % retention of the original capacitance after 10,000 cycles), the manufactured MCS@MCO/rGO//AC ACS displays an impressive energy density of 57.5 Whkg-1. The mesoporous structure is excellent for increasing the characteristics of supercapacitor electrodes, as these astounding results can demonstrate.

Storage and Transportation of Hythane: Thermodynamics, Kinetics, and Stability Studies Using the Gas Hydrates Process

Storage and Transportation of Hythane: Thermodynamics, Kinetics, and Stability Studies Using the Gas Hydrates Process

γ-Cyclodextrin-metal organic framework as a carrier for trans-N-p-coumaroyltyramine: A study of drug solubability, stability, and inhibitory activity against α-glucosidase.

γ-Cyclodextrin-based metal-organic frameworks (γ-CD-MOF) were successfully synthesized using the solvent diffusion method and applied as carriers for trans-N-p-coumaroyltyramine (N-p-t-CT, NCT) to study the solubability, stability, sustained release and inhibitory activity against α-glucosidase. The solubilization effect of γ-CD-MOF on N-p-t-CT was performed using impregnation (NCT@CD-MOF-1) and co-crystallization (NCT@CD-MOF-2) methods. X-ray diffraction, scanning electron microscope (SEM), fourier transform infrared spectrometer (FTIR), and N2 adsorption/desorption were used to characterize the MOFs before and after loading NCT. The results showed that NCT@CD-MOF-2 had a better solubability for N-p-t-CT, 145.03μg/mg of drug loading capacity could be achieved, and the solubility of NCT@CD-MOF-2 in water was 366 times higher than free N-p-t-CT. In addition, the stabilities of N-p-t-CT under temperature, UV light and pH conditions were greatly improved after encapsulation in γ-CD-MOF. Furthermore, NCT@CD-MOFs had a sustained release of N-p-t-CT over an extended period in vitro due to the primary encapsulation in pore structures. Notably, γ-CD-MOF loaded with N-p-t-CT showed superior inhibitory activity against α-glucosidase compared to free N-p-t-CT. Cytotoxicity studies demonstrated that NCT@CD-MOF-2 had low toxicity in vitro and perfect biocompatibility with HL-7702 cells, and γ-CD-MOF could reduce the toxicity of free N-p-t-CT at higher concentrations.

Ensuring Stability of Anode Catalysts in PEMWE: From Material Design to Practical Application.

Proton Exchange Membrane Water Electrolysis (PEMWE) has emerged as a clean and effective approach for the conversion and storage of renewable electricity, particularly due to its compatibility with fluctuating photovoltaic and wind power. However, the high cost and limited performance of iridium oxide catalysts (i.e. IrO2) used as anode catalyst in industrial PEM electrolyzers remain significant obstacles to widespread application. Although numerous low-cost and efficient alternative catalysts have been developed in laboratory research, comprehensive stability studies critical for industrial use are often overlooked. This leads to the failure of performance transfer from catalysts tested in liquid half-cell systems to those employed in PEM electrolyzers. This concept presents a thorough overview for the stability issues of anode catalysts in PEMWE, and discuss their degradation mechanisms in both liquid half-cell systems and PEM electrolyzers. We summarize comprehensive protocol for the assessment and characterization, analyze the effective strategies for stability optimization, and explore the opportunities for designing viable anode catalysts for PEM electrolyzers.

Consequences of slope instability and existing practices of mitigation in hydropower projects of Nepal

IntroductionNepal has witnessed several instances of slope instability associated with Hydroelectric Projects in the recent decades. Despite this, slope instability tends to receive less attention compared to other hazards.ObjectivesThe objective of this study is to investigate fourteen hydroelectric projects with the aim of identifying the types and causes of slope failures. Additionally, it seeks to offer a comprehensive understanding of slope stability conditions and challenges encountered during construction at project sites.MethodsTo accomplish this, the study employs Key Informant Interviews with Questionnaires to delve into the slope stability concerns within Nepal’s hydropower projects. The findings are then validated through an extensive review of pertinent literature. To conduct a thorough assessment of slope stability, the study relies on on-site observations, measurements, investigations, and both in-situ and laboratory tests.ResultsIt becomes evident that the careful selection of study sites, the application of geotechnical methods, and the establishment of regular monitoring are pivotal for ensuring favorable slope stability outcomes.ConclusionA majority of respondents concur that cutslope is the primary factor causing slope instability with 44.4% answering affirmatively. An independent t-test reveals there is no significant difference between the variables. Moreover, the correlation which is closed to 1 suggests that perception of respondents are interconnected and tend to vary in a synchronized manner. Participants in the study widely acknowledge numerical modeling methods as a means to overcome the limitations of slope stability studies.

Preparation and Stability Study of an Injectable Hydrogel for Artificial Intraocular Lenses

Currently available intraocular lenses (IOLs) on the market often differ significantly in elastic modulus compared to the natural human lens, which impairs their ability to respond effectively to the tension of the ciliary muscles for focal adjustment after implantation. In this study, we synthesized a polyacrylamide–sodium acrylate hydrogel (PAH) through the cross-linking polymerization of acrylamide and sodium acrylate. This hydrogel possesses excellent biocompatibility and exhibits several favorable properties. Notably, the hydrogel demonstrates high transparency (94%) and a refractive index (1.41 ± 0.07) that closely matches that of the human lens (1.42). Additionally, it shows strong compressive strength (14.00 kPa), good extensibility (1400%), and an appropriate swelling ratio (50 ± 2.5%). Crucially, the tensile modulus of the hydrogel is 2.07 kPa, which closely aligns with the elastic modulus of the human lens (1.70–2.10 kPa), enabling continuous focal adjustment under the tension exerted by the ciliary muscles.

A selective, sensitive and fast LC-MS/MS method for cabotegravir quantification in rat plasma and pharmacokinetic investigations.

This study presents a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying cabotegravir (CAB) in rat plasma. A novel, sensitive, and rapid LC-MS/MS method has been developed and validated. Furthermore, protein precipitation technique allowed us to lowered the limit of quantification (LOQ) to nanogram levels, allowing detection of smaller CAB amounts in plasma samples. A review of scientific literature reveals that this method is superior than published methods in terms of runtime, sensitivity, wide linearity, and cost, using LC-MS/MS to quantify CAB in biological samples. CAB reached its maximum concentration (Cmax) of 78.401 μg/mL in rat plasma at 1.50 h (Tmax). Linearity was evaluated across 0.05-1000 μg/mL for CAB using five calibration curves with at least nine standards each with r2 > 0.9997. The intra- and inter-day precision and accuracy results were below 15% and acceptable as per Food and Drug Administration (FDA) guidelines. Stability of compounds were established in a battery of stability studies, that is, benchtop, autosampler, and long-term storage stability as well as freeze thaw cycles. The validated method can be used as a routine method to support pharmacokinetic studies.

Discovery and structure − activity relationships of 2,4,5-trimethoxyphenyl pyrimidine derivatives as selective D5 receptor partial agonists

Dopamine receptors are therapeutic targets for the treatment of various neurological and psychiatric disorders, including Parkinson’s and Alzheimer’s. Previously, PF-06649751 (tavapadon), PF-2562 and PW0464 have been discovered as potent and selective G protein-biased D1/D5 receptor agonists with optimal pharmacokinetic properties. However, no selective D5R agonist has been reported yet. In this context, we designed and synthesized forty non-catecholamines-based pyrimidine derivatives and identified four pyrimidine derivatives as selective D5R partial agonists. Using cAMP-based GloSensor assay in transiently transfected HEK293T cells with human D1 or D5 receptors, we discovered that compound 5c (4-(4-bromophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-amine) exhibited modest D5R agonist activity. This leads us to explore various modifications of this scaffold to improve the D5 agonist potency and efficacy. Using molecular docking, and rational design followed by their evaluation at D1 and D5 receptors for agonist activity, we identified three new derivatives, 5j, 5h, and 5e. The most potent compound of this series 5j (4-(4-iodophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-amine), exhibited EC50 of 269.7 ± 6.6 nM. Mice microsomal stability studies revealed that 5j is quite stable (>70 % at 1 hr). Furthermore, pharmacokinetic analysis of 5j (20 mg/kg, p.o) in C57BL/6j mice showed that 5j is readily absorbed via oral route of dosing and also enters into the brain (plasma Tmax: 1 h, Cmax: 51.10 ± 13.51 ng/ml; Brain Tmax: 0.5 h, Cmax: 22.54 ± 4.08 ng/ml). We further determined the in-vivo effect of 5j on cognition in scopolamine-induced amnesia in C57BL/6j mice. We observed that 5j (10 mg/kg, p.o) alleviated scopolamine-induced impairment in short-term memory and social recognition, which were blocked by D1/D5 antagonist SCH23390 (0.1 mg/kg, i.p.). Furthermore, 5j did not exhibit any cytotoxicity (up to 10 µM) or in vivo acute toxicity up to 200 mg/kg (p.o). These results strongly suggest that 5j could be further developed for treating neurological disorders wherein the D5 receptors play pivotal roles.