RESUMEN
The R3m molecular descriptor (R-GETAWAY third-order autocorrelation index weighted by the atomic mass) has previously been shown to encode molecular attributes that appear to be physically and chemically relevant to grouping diverse active pharmaceutical ingredients (API) according to their potential to form persistent amorphous solid dispersions (ASDs) with polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA). The initial R3m dispersibility model was built by using a single three-dimensional (3D) conformation for each drug molecule. Since molecules in the amorphous state will adopt a distribution of conformations, molecular dynamics simulations were performed to sample conformations that are probable in the amorphous form, which resulted in a distribution of R3m values for each API. Although different conformations displayed R3m values that differed by as much as 0.4, the median of each R3m distribution and the value predicted from the single 3D conformation were very similar for most structures studied. The variability in R3m resulting from the distribution of conformations was incorporated into a logistic regression model for the prediction of ASD formation in PVPVA, which resulted in a refinement of the classification boundary relative to the model that only incorporated a single conformation of each API.
Asunto(s)
Polímeros , Povidona , Polímeros/química , Povidona/química , Compuestos de Vinilo/química , Liberación de Fármacos , Solubilidad , Composición de Medicamentos/métodosRESUMEN
We propose a simulation method for a multireflector terahertz imaging system. The description and verification of the method are based on an existing active bifocal terahertz imaging system at 0.22 THz. Using the phase conversion factor and angular spectrum propagation, the computation of the incident and received fields requires only a simple matrix operation. The phase angle is used to calculate the ray tracking direction, and the total optical path is used to calculate the scattering field of defective foams. Compared with the measurements and simulations of aluminum disks and defective foams, the validity of the simulation method is confirmed in the field of view of 50â cm × 90â cm at 8 m. This work aims to develop better imaging systems by predicting their imaging behavior for different targets before manufacturing.
RESUMEN
A molecular descriptor known as R3m (the R-GETAWAY third-order autocorrelation index weighted by the atomic mass) was previously identified as capable of grouping members of an 18-compound library of organic molecules that successfully formed amorphous solid dispersions (ASDs) when co-solidified with the co-polymer polyvinylpyrrolidone vinyl acetate (PVPva) at two concentrations using two preparation methods. To clarify the physical meaning of this descriptor, the R3m calculation is examined in the context of the physicochemical mechanisms of dispersion formation. The R3m equation explicitly captures information about molecular topology, atomic leverage, and molecular geometry, features which might be expected to affect the formation of stabilizing non-covalent interactions with a carrier polymer, as well as the molecular mobility of the active pharmaceutical ingredient (API) molecule. Molecules with larger R3m values tend to have more atoms, especially the heavier ones that form stronger non-covalent interactions, generally, more irregular shapes, and more complicated topology. Accordingly, these molecules are more likely to remain dispersed within PVPva. Furthermore, multiple linear regression modeling of R3m and more interpretable descriptors supported these conclusions. Finally, the utility of the R3m descriptor for predicting the formation of ASDs in PVPva was tested by analyzing the commercially available products that contain amorphous APIs dispersed in the same polymer. All of these analyses support the conclusion that the information about the API geometry, size, shape, and topological connectivity captured by R3m relates to the ability of a molecule to interact with and remain dispersed within an amorphous PVPva matrix.
Asunto(s)
Composición de Medicamentos/métodos , Liberación de Fármacos , Povidona/química , Compuestos de Vinilo/química , Modelos Químicos , Estructura MolecularRESUMEN
The purpose of this study is to develop a classification system utilizing milligram amounts of the compound for physical stability ranking of amorphous pharmaceuticals, which can be used as an early risk assessment tool for amorphous solid dispersion formulations. Simple thermal analysis utilizing a differential scanning calorimeter is used to characterize amorphous pharmaceuticals with respect to their molecular mobility and configurational entropy. Molecular mobility and configurational entropy are considered as two critical factors in determining the physical stability of amorphous phases. Theoretical arguments and numerical simulations suggest that the fragility strength parameter is a good indicator of the molecular mobility below Tg, and the heat capacity change at Tg is a good indicator of the configurational entropy. Using these two indicators, 40 structurally diverse pharmaceuticals with known physical stability were analyzed. Four classes of compounds are defined with class I being the most stable and class IV the least stable. The proposed amorphous classification system and methodology for estimating molecular mobility and configurational entropy provides an easily accessible framework to conduct early risk assessments related to physical stability challenges in developing amorphous formulations.
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Preparaciones Farmacéuticas/química , Rastreo Diferencial de Calorimetría , Cristalización , Estabilidad de Medicamentos , Cinética , Solubilidad , TermodinámicaRESUMEN
Modeling of the lyophilization process, based on the steady-state heat and mass transfer, is a useful tool in understanding and optimizing of the process, developing an operating design space following the quality-by-design principle, and justifying occasional process deviations during routine manufacturing. The steady-state model relies on two critical parameters, namely, the vial heat transfer coefficient, Kv, and the cake resistance, Rp. The classical gravimetric method used to measure Kv is tedious, time- and resource-consuming, and can be challenging and costly for commercial scale dryers. This study proposes a new approach to extract both Kv and Rp directly from an experimental run (e.g., temperature and Pirani profiles). The new methodology is demonstrated using 5% w/v mannitol model system. The values of Kv obtained using this method are comparable to those measured using the classic gravimetric method. Application of the proposed approach to process scale-up and technology transfer is illustrated using a case study. The new approach makes the steady-state model a simple and reliable tool for model parameterization, thus maximizes its capability and is particularly beneficial for transfer products from lab/pilot to commercial manufacturing.
Asunto(s)
Liofilización/métodos , Transferencia de Tecnología , Tecnología Farmacéutica/métodos , TemperaturaRESUMEN
This paper introduces a method for optimizing the terahertz (THz) imaging resolution in a specified field of view (FoV) for a scanning dual reflector system (Gregory or Cassegrain system) based on the theory of field curvature. The authors built a Gregory scanning system to verify the ability of this method. The operating frequency of the verification system is 220 GHz, the FoV at a specified distance of 8 m is approximately 50 cm * 100 cm, and the imaging resolution throughout the entire FoV is better than 3 cm. Experimental results show that the imaging resolution of the classical dual reflector system can be optimized, and the proposed verification system can realize active THz imaging of the human body.
RESUMEN
This paper introduces a dual-band terahertz imaging system as a potential product for nondestructive testing using heterodyne detectors and continuous-wave sources. The operating frequencies of the system are 110.4 and 220.8 GHz. Multiband fusion technology combines the advantages of the greater spatial resolution of the high-frequency band and the enhanced sensitivity of the low-frequency band to improve the detection ability of the system. Additionally, the interference cancellation technology is used to obtain a superior image quality. The spatial resolution of this system was approximately 3 mm. The results show that the system can be used for bonding quality and embedded defect detection in radomes and foam materials adhered to metal plates in aircrafts.
RESUMEN
We propose a mechanism that there are matching relations between mRNA sequences and corresponding post-spliced introns, and introns play a significant role in the process of gene expression. In order to reveal the sequence matching features, Smith-Waterman local alignment method is used on C. elegans mRNA sequences to obtain optimal matched segments between exon-exon sequences and their corresponding introns. Distribution characters of matching frequency on exon-exon sequences and sequence characters of optimal matched segments are studied. Results show that distributions of matching frequency on exon-exon junction region have obvious differences, and the exon boundary is revealed. Distributions of the length and matching rate of optimal matched segments are consistent with sequence features of siRNA and miRNA. The optimal matched segments have special sequence characters compared with their host sequences. As for the first introns and long introns, matching frequency values of optimal matched segments with high GC content, rich CG dinucleotides and high λCG values show the minimum distribution in exon junction complex (EJC) binding region. High λCG values in optimal matched segments are main characters in distinguishing EJC binding region. Results indicate that EJC and introns have competitive and cooperative relations in the process of combining on protein coding sequences. Also intron sequences and protein coding sequences do have concerted evolution relations.
Asunto(s)
Caenorhabditis elegans/genética , Exones , Intrones , Animales , Secuencia de Bases , Biología Computacional , Regulación de la Expresión Génica , MicroARNs/metabolismo , Modelos Genéticos , Datos de Secuencia Molecular , Nucleótidos/genética , Empalme del ARN , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismoRESUMEN
Amorphous solid dispersion (ASD) is an enabling approach utilized to deliver poorly soluble compounds. ASDs can spontaneously generate drug-rich amorphous nanoparticles upon dissolution, which can act as a reservoir for maintaining supersaturation during oral absorption. But, conventional ASDs are often limited in drug loadings to < 20 %. For indications where the dose is high, this can translate into a significant pill burden. The aim of this research was to develop a high drug loading (DL) amorphous nanoparticle (ANP) formulation that can release the drug-rich nanoparticles into solution upon contact with aqueous environment. Nanoparticles were directly engineered using solvent/anti-solvent precipitation. The obtained nanoparticle suspension was then concentrated followed by solidification to a re-dispersible amorphous dosage form using spray drying or lyophilization. The impact of process variables was studied using dynamic light scattering (DLS), scanning electron microscopy (SEM), high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) and differential scanning calorimetry (DSC). It was observed that spray drying led to a non-re-dispersible formulation. Sucrose and trehalose containing lyocakes resulted in re-dispersible formulations. The trehalose containing lyocakes, in a dog study, gave comparable performance to the reference tablet in the fasted state but lower area under the curve (AUC) in fed state.
Asunto(s)
Nanopartículas , Trehalosa , Animales , Perros , Solubilidad , Solventes , Agua/química , Nanopartículas/química , Composición de Medicamentos/métodos , Liberación de FármacosRESUMEN
Evaluation of different amorphous solid dispersion carrier matrices is enabled by active pharmaceutical ingredient (API) structure-based predictions. This study compares the utility of Hansen Solubility Parameters with the R3m molecular descriptor for identifying dispersion polymers based on the structure of the drug molecule. Twelve API-polymer combinations (4 APIs and 3 interrelated polymers) were used to test each approach. Co-solidified mixtures containing 75% API were prepared by melt-quenching. Phase behavior was evaluated and classified using differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, and hot stage microscopy. Observations of dispersion behavior were compared to predictions made using the Hansen Solubility Parameter and R3m. The solubility parameter approach misclassified the dispersion behavior of 1 API-polymer combination and also did not produce definite predictions in 3 out of 12 of the API-polymer combinations. In contrast, R3m classifications of dispersion behavior were correct in all but two cases, with one misclassification and one ambiguous prediction. The solubility parameters best classify dispersion behavior when specific drug-polymer intermolecular interactions are present, but may be less useful otherwise. Ultimately, these two methods are most effectively used together, as they are based on distinct features of the same molecular structure.
Asunto(s)
Polímeros , Povidona , Rastreo Diferencial de Calorimetría , Química Farmacéutica/métodos , Composición de Medicamentos/métodos , Polímeros/química , Povidona/química , SolubilidadRESUMEN
Amorphous solid dispersions (ASD) are a commonly used enabling formulation technology to drive oral absorption of poorly soluble drugs. To ensure adequate solid-state stability and dissolution characteristics, the ASD formulation design typically has ≤ 25% drug loading. Exposed to aqueous media, ASD formulations can produce drug-rich colloidal dispersion with particle size < 500 nm. This in situ formation of colloidal particles requires incorporation of excess excipients in the formulation. The concept of using engineered drug-rich particles having comparable size as those generated by ASDs in aqueous media is explored with the goal of increasing drug loading in the solid dosage form. Utilizing ABT-530 as model compound, a controlled solvent-antisolvent precipitation method resulted in a dilute suspension that contained drug-rich (90% (w/w)) amorphous nanoparticles (ANP). The precipitation process was optimized to yield a suspension containing < 300 nm ANP. A systematic evaluation of formulation properties and process variables resulted in the generation of dry powders composed of 1-8 µm agglomerates of nanoparticles which in contact with water regenerated the colloidal suspension having particle size comparable to primary particles. Thus, this work demonstrates an approach to designing a re-dispersible ANP based powder containing ≥90% w/w ABT-530 that could be used in preparation of a high drug load solid dosage form.
Asunto(s)
Agua , Composición de Medicamentos/métodos , Liberación de Fármacos , Tamaño de la Partícula , Polvos , Solubilidad , SuspensionesRESUMEN
Management of tailings at metal mine smelter sites can reduce the potential hazards associated with exposure to toxic metal(loid)s and residual organic flotation reagents. In addition, microbes in the tailings harboring multi-resistance genes (e.g., tolerance to multiple antimicrobial agents) can cause high rates of morbidity and global economic problems. The potential co-selection mechanisms of antibiotic resistance genes (ARGs) and metal(loid) resistance genes (MRGs) during tailings sulfate-reducing bacteria (SRB) treatment have been poorly investigated. Samples were collected from a nonferrous metal mine tailing site treated with an established SRB protocol and were analyzed for selected geochemical properties and high throughput sequencing of 16S rRNA gene barcoding. Based on the shotgun metagenomic analysis, the bacterial domain was dominant in nonferrous metal(loid)-rich tailings treated with SRB for 12 months. KEGGs related to ARGs and MRGs were detected. Thiobacillus and Sphingomonas were the main genera carrying the bacA and mexEF resistance operons, along with Sulfuricella which were also found as the main genera carrying MRGs. The SRB treatment may mediate the distribution of numerous resistance genes. KOs based on the metagenomic database indicated that ARGs (mexNW, merD, sul, and bla) and MRGs (czcABCR and copRS genes) were found on the same contig. The SRB strains (Desulfosporosinus and Desulfotomaculum), and the acidophilic strain Acidiphilium significantly contributed to the distribution of sul genes. The functional metabolic pathways related to siderophores metabolism were largely from anaerobic genera of Streptomyces and Microbacterium. The presence of arsenate reductase, metal efflux pump, and Fe transport genes indicated that SRB treatment plays a key role in the metal(loid)s transformation. Overall, our findings show that bio-treatment is an effective tool for managing ARGs/MRGs and metals in tailings that contain numerous metal(loid) contaminants.
Asunto(s)
Bacterias , Metales , ARN Ribosómico 16S , Metales/análisis , Bacterias/metabolismo , Antibacterianos/farmacología , China , Sulfatos/análisis , Genes BacterianosRESUMEN
BP neural network (BPNN), as a multilayer feed-forward network, can realize the deep cognition to target data and high accuracy to output results. However, there were still no related research of k-mer based on BPNN yet. In present study, BPNN was used to train and test binary classification data of each classification mode respectively. All k-mer were divided into two categories according to the X + Y content or completely random mode. Results showed that 1) For classification mode of X + Y content, the accuracy of k-mers classification was 100 percent, no matter k ≤ 6 or k ≥ 7; 2) For completely random classification mode, the accuracy of classification is 100 percent for k-mers of k ≤ 6; But for k-mers of k ≥ 7, the accuracy is less than 100 percent, and with the increase of k value, the accuracy of classification gradually decreases (gradually approaches 50 percent). The k-mers of k ≥ 7 should be the basic functional fragment of nucleic acid, and perform basic nucleic acid function in the DNA sequence. The k-mers of k ≤ 6 should be the basic component fragment of nucleic acid, and no longer perform basic nucleic acid function.
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Redes Neurales de la Computación , Ácidos Nucleicos , Algoritmos , Secuencia de Bases , Análisis de Secuencia de ADNRESUMEN
Nucleosome localization is a dynamic process and consists of nucleosome dynamic intervals (NDIs). We preprocessed nucleosome sequence data as time series data (TSD) and developed a long short-term memory network (LSTM) model for training time series data (TSD; LSTM-TSD model) using iterative training and feature learning that predicts NDIs with high accuracy. Sn, Sp, Acc, and MCC of the obtained LSTM model is 91.88%, 92.72%, 92.30%, and 84.61%, respectively. LSTM model could precisely predict the NDIs of yeast 16 chromosome. The NDIs contain 90.29% of nucleosome core DNA and 91.20% of nucleosome central sites, indicating that NDIs have high confidence. We found that the binding sites of transcriptional proteins and other proteins are outside NDIs, not in NDIs. These results are important for analysis of nucleosome localization and gene transcriptional regulation.
Asunto(s)
Redes Neurales de la Computación , Nucleosomas , Memoria a Corto Plazo , Nucleosomas/genéticaRESUMEN
PURPOSE: To investigate the underlying physical processes taking place during dissolution of amorphous pharmaceuticals and correlate them to the observed solution concentration-time profiles. Felodipine and indomethacin were used as model hydrophobic compounds. METHODS: Concentration-time profiles were monitored during dissolution of the model amorphous compounds using in situ fiber-optic ultraviolet spectroscopy. Crystallization of the solid exposed to an aqueous environment was monitored using Raman spectroscopy and/or powder X-ray diffraction. Polarized light microscopy was used to provide qualitative information about crystallization processes. RESULTS: For felodipine, a small extent of supersaturation was generated via dissolution at 25 degrees C but not at 37 degrees C. The amorphous solid was found to crystallize rapidly at both temperatures upon exposure to the dissolution medium. Addition of low concentrations of polymers to the dissolution medium was found to delay crystallization of the amorphous solid, leading to the generation of supersaturated solutions. Amorphous indomethacin did not crystallize as readily in an aqueous environment; hence, dissolution resulted in supersaturated solutions. However, crystallization from these supersaturated solutions was rapid. Polymeric additives were able to retard crystallization from supersaturated solutions of both indomethacin and felodipine for up to 4 h. CONCLUSIONS: The dissolution advantage of amorphous solids can be negated either by crystallization of the amorphous solid on contact with the dissolution medium or through rapid crystallization of the supersaturated solution. Polymeric additives can potentially retard both of these crystallization routes, leading to the generation of supersaturated solutions that can persist for biologically relevant timeframes.
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Felodipino/química , Indometacina/química , Cristalización , Difracción de Polvo , Solubilidad , Espectrometría Raman , Difracción de Rayos XRESUMEN
Dynamics of +1 and -1 nucleosomes near TSS of yeast chromosome 2 were analyzed by using second-order information entropy and density functional theory method. Second-order information entropy can measure the interaction intensity between nucleosome sequences and nucleosome histones based on the intensity of base association. In addition, density functional theory method can be used to obtain the global interaction intensity between nucleosome sequences and nucleosome histones based on energy state size and active or non-active state of binucleoside pairs. Our results showed asymmetry of interaction intensity on both sides of the nucleosome central site, and that +1 nucleosomes tend to move toward the 5'-end and -1 nucleosomes tend to move toward the 3'-end. Under the dynamic balance of nucleosome movement, in roder to shut down gene transcription, +1 and -1 nucleosomes will cover TSS. If the dynamic balance is destroyed, +1 and -1 nucleosomes stay away from each other to expose TSS to restart gene transcription. The movement trend of +1 and -1 nucleosomes coincides with the biological mechanism of gene transcription and non-transcription, and the nucleosome sequences contain the dynamic information of nucleosome movement, which provides effective technical support for the study of gene transcription regulation mechanism.
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Entropía , Nucleosomas/metabolismo , Ensamble y Desensamble de Cromatina , Teoría Funcional de la Densidad , Regulación de la Expresión Génica , Transcripción GenéticaRESUMEN
Mine tailings sites are considered as a continuous source of discharged metal(loid)s and residual organic flotation reagents. They are extremely toxic environments representing unique ecological niches for microbial communities. Mine tailings as a source of multi-resistance genes have been poorly investigated. Metagenomic analysis for four active nonferrous metal(loid) tailings sites with different environmental parameters was conducted. The abundance of Thiobacillus, able to tolerate acidity and showing iron- and sulfur/sulfide oxidation capacities, was significantly different (p < 0.05) between acid and neutral tailings sites. Correlation analyses showed that Zn, Pb, TP, Cd, and Cu were the main drivers influencing the bacterial compositions. Multi-metal resistance genes (MRGs) and antibiotic resistance genes (ARGs), such as baca and copA, were found to be co-selected by high concentrations of metal(loid)s tailings. The main contributors to different distributions of MRGs were Thiobacillus and Nocardioides genus, while genera with low abundance (<0.1%) were the main contributors for ARGs. Functional metabolic pathways related to Fe-S metabolism, polycyclic aromatic hydrocarbons (PAHs) degradation and acid stress were largely from Altererythrobacter, Lysobacter, and Thiobacillus, respectively. Such information provides new insights on active tailings with highly toxic contaminants. Short-term metal(loid) exposure of microorganism in active nonferrous metal(loid) tailings contribute to the co-occurrence of ARGs and MRGs, and aggravation of tailings acidification. Our results recommend that the management of microorganisms involved in acid tolerance and metal/antibiotic resistance is of key importance for in-suit treatment of the continuous discharge of tailings with multiple metal(loid) contaminants into impoundments.
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Scale-up and technology transfer of lyophilization processes remains a challenge that requires thorough characterization of the laboratory and larger scale lyophilizers. In this study, computational fluid dynamics (CFD) was employed to develop computer-based models of both laboratory and manufacturing scale lyophilizers in order to understand the differences in equipment performance arising from distinct designs. CFD coupled with steady state heat and mass transfer modeling of the vial were then utilized to study and predict independent variables such as shelf temperature and chamber pressure, and response variables such as product resistance, product temperature and primary drying time for a given formulation. The models were then verified experimentally for the different lyophilizers. Additionally, the models were applied to create and evaluate a design space for a lyophilized product in order to provide justification for the flexibility to operate within a certain range of process parameters without the need for validation.
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Simulación por Computador , Liofilización/métodos , Transferencia de Tecnología , Tecnología Farmacéutica/métodos , Química Farmacéutica , Desecación/instrumentación , Desecación/métodos , Liofilización/instrumentación , Calor , Hidrodinámica , Laboratorios , Presión , Tecnología Farmacéutica/instrumentación , Agua/químicaRESUMEN
A new structural series of histamine H3 receptor antagonist was developed. The new compounds are based on a quinoline core, appended with a required basic aminoethyl moiety, and with potency- and property-modulating heterocyclic substituents. The analogs have nanomolar and subnanomolar potency for the rat and human H3R in various in vitro assays, including radioligand competition binding as well as functional tests of H3 receptor-mediated calcium mobilization and GTPgammaS binding. The compounds possessed favorable drug-like properties, such as good PK, CNS penetration, and moderate protein binding across species. Several compounds were found to be efficacious in animal behavioral models of cognition and attention. Further studies on the pharmaceutic properties of this series of quinolines discovered a potential problem with photochemical instability, an issue which contributed to the discontinuation of this series from further development.
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Pirazoles/síntesis química , Pirimidinas/síntesis química , Quinolinas/síntesis química , Receptores Histamínicos H3/metabolismo , Animales , Atención/efectos de los fármacos , Reacción de Prevención/efectos de los fármacos , Proteínas Sanguíneas/metabolismo , Barrera Hematoencefálica/metabolismo , Calcio/metabolismo , Línea Celular , Cognición/efectos de los fármacos , Perros , Agonismo Inverso de Drogas , Estabilidad de Medicamentos , Haplorrinos , Humanos , Unión Proteica , Pirazoles/farmacocinética , Pirazoles/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Quinolinas/farmacocinética , Quinolinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas SHR , Reconocimiento en Psicología/efectos de los fármacos , Conducta Social , Estereoisomerismo , Relación Estructura-Actividad , Distribución TisularRESUMEN
Three novel heterocyclic benzofurans A-688057 (1), A-687136 (2), and A-698418 (3) were profiled for their in vitro and in vivo properties as a new series of histamine H(3) receptor antagonists. The compounds were all found to have nanomolar potency in vitro at histamine H(3) receptors, and when profiled in vivo for CNS activity, all were found active in an animal behavioral model of attention. The compound with the most benign profile versus CNS side effects was selected for greater scrutiny of its in vitro properties and overall drug-likeness. This compound, A-688057, in addition to its potent and robust efficacy in two rodent behavioral models at blood levels ranging 0.2-19 nM, possessed other favorable features, including high selectivity for H(3) receptors (H(3), K(i)=1.5 nM) versus off-target receptors and channels (including the hERG K(+) channel, K(i)>9000 nM), low molecular weight (295), high solubility, moderate lipophilicity (logD(pH7.4)=2.05), and good CNS penetration (blood/brain 3.4x). In vitro toxicological tests indicated low potential for phospholipidosis, genotoxicity, and CYP(450) inhibition. Even though pharmacokinetic testing uncovered only moderate to poor oral bioavailability in rat (26%), dog (30%), and monkey (8%), and only moderate blood half-lives after i.v. administration (t(1/2) in rat of 2.9h, 1.7h in dog, 1.8h in monkey), suggesting poor human pharmacokinetics, the data overall indicated that A-688057 has an excellent profile for use as a pharmacological tool compound.