Opioid analgetics retention-pharmacologic activity models using biopartitioning micellar chromatography

Opioids are drugs used in medicine for pain control. In this paper, retention-pharmacokinetics and retention-pharmacodynamics relationships of opioids are proposed and statistically validated. These models are based on the compound retention in the biopartitioning micellar chromatography system (BMC), a new methodology which has successfully been used to develop QRAR models for many other families of compounds. The obtained results are compared to the traditional QSAR models using lipophilicity data. The adequacy of QRAR models is due to the fact that the characteristics of the compounds such as the hydrophobicity, electronic charge and steric effects determine both their retention in BMC and their pharmacokinetic and pharmacodynamic behavior.     

Role of hydrophobicity on the monoamine receptor binding affinities of central nervous system drugs: a quantitative retention-activity relationships analysis using biopartitioning micellar chromatography

Biological action and activity reflect an aspect of the fundamental physicochemical properties of the bioactive compounds. As an alternative to classical QSAR studies, in this work different quantitative retention-activity relationships (QRAR) models are proposed, which are able to describe the role of hydrophobicity on the binding affinity to different brain monoamine receptors (H(1)-histamine, alpha(1)-noradrenergic and 5-HT(2)-serotonergic) of different families of psychotherapeutic drugs. The retention of compounds is measured in a biopartitioning micellar chromatography (BMC) system using Brij-35 mobile phases. The adequacy of the QRAR models developed is due to the fact that both the retention of compounds in BMC and the drug-receptor interaction are described by the same hydrophobic, electronic and steric properties of compounds. The obtained results indicate that, for structurally related compounds that present the same molecular features as the basic pharmacophore, there is a retention range in which compounds present the highest affinity to all of monoamine receptors.     

QRAR models for cardiovascular system drugs using biopartitioning micellar chromatography

The capability of biopartitioning micellar chromatography (BMC) to describe and estimate pharmacological parameters of cardiovascular system drugs has been studied. The retention of cardiovascular system drugs was studied using different pH of Brij-35 as micellar mobile phase in modified C(18) stationary phase. Quantitative retention-activity relationships (QRAR) in BMC were investigated for these compounds. An adequate correlation between the retention factors (log k) and the toxicity (LD(50)) of cardiovascular system drugs was obtained.     

Short-acting 5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one derivatives as orally-active calcium-sensing receptor antagonists

Synthesis and structure–activity relationship (SAR) studies on 5-trifluoromethylpyrido[4,3-d]pyrimidin-4(3H)-ones, a novel class of calcium receptor antagonists is described with particular emphasis on optimization of the pharmacokinetic/pharmacodynamic parameters required for a short duration of action compound. Orally-active compounds were identified which displayed the desired animal pharmacology (rapid and transient stimulation of parathyroid hormone) essential for bone anabolic effects.     

Chromatographic evaluation of the toxicity in fish of pesticides

Ecotoxicity assessment is essential before placing new chemical substances on the market. An investigation of the use of the chromatographic retention (log k) in biopartitioning micellar chromatography (BMC) as an in vitro approach to evaluate the toxicity in fish of pesticides (acute toxicity levels as pLC(50)) is proposed. A heterogeneous data set of 85 pesticides from six chemical families with available experimental fish toxicity data (ECOTOX database from U.S. Environmental Protection Agency (EPA)) was used. For pesticides exhibiting non-polar narcosis mechanism in fish (non-specific toxicity), more reliable models and precise pLC(50) estimations are obtained from log k (quantitative retention-activity relationships, QRAR) than from log P (quantitative structure-activity relationships, QSAR) or ECOSAR (ECOSAR program from U.S. EPA).     

Chemometric modelling of antimalarial activity of aryltriazolylhydroxamates

We have performed quantitative structure–activity relationship (QSAR) and quantitative activity–activity relationship (QAAR) studies for aryltriazolylhydroxamates having antimalarial activity data against both chloroquine-sensitive (D6 clone) and chloroquine-resistant (W2 clone) strains of Plasmodium falciparum to understand the relationships between the biological activity and molecular properties for the design of new compounds. The QSAR studies were performed using 35 compounds among which 26 molecules were taken using k-means clustering technique in the training set for the derivation of the QSAR models and nine molecules were kept as the test-set compounds to evaluate the predictive ability of the derived models. The chemometric tool used for the analysis was the genetic function approximation. The developed models were analysed in terms of their predictive ability, and comparable results were obtained for cross-validated predictive variance (Q ²) and externally predicted variance (R ² _pred) values (0.761 and 0.829, respectively, for the D6 model, 0.708 and 0.748, respectively, for the W2 model and 0.984 and 0.982, respectively for the QAAR model). The QSAR models suggest that the number of methylene groups (between the triazolyl and hydroxamate moieties) and partially negatively charged surface areas of the molecules are important parameters for the antimalarial activity.     

Carbazole-containing amides and ureas: Discovery of cryptochrome modulators as antihyperglycemic agents

A series of novel carbazole-containing amides and ureas were synthesized. A structure–activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the desired pharmacokinetic/pharmacodynamic parameters and the results of efficacy studies in db/db mice, compound 50 was selected for further profiling.     

Retention–property relationships of anticonvulsant drugs by biopartitioning micellar chromatography

Epilepsy may be considered as a group of disorders with only one thing in common: the fact that recurrent anomalous electrochemical phenomena appear in the central nervous system. Different classes of drugs are included under the generic term of anticonvulsant drugs. All of them work by decreasing discharge propagation in different ways. Biopartitioning micellar chromatography (BMC) is a mode of reversed-phase liquid chromatography, which can be used as an in vitro system to model the biopartitioning process of drugs when there are no active processes. In this paper, relationships between the BMC retention data of anticonvulsant drugs, their pharmacokinetics (oral absorption, protein binding, volume of distribution, clearance, and renal elimination) and their therapeutic parameters (therapeutic, toxic and comatose-fatal concentration, and LD₅₀) are studied and the predictive ability of models is evaluated.     

Quantitative structure–activity relationship of substituted imidazothiadiazoles for their binding against the ecdysone receptor of Sf-9 cells

Imidazothiadiazoles (ITDs) are a class of potent nonsteroidal ecdysone agonists with larvicidal activity. Previously, we performed the Hansch–Fujita type of quantitative structure–activity relationship (QSAR) analysis for ITD analogs (Yokoi et al., Pestic. Biochem. Physiol.2015, 120, 40–50). The activity was reasonably explained by hydrophobicity and electronegativity of substituents on the imidazothiadiazole ring system. However, the limited data points (n?=?8) hampered the examination of other physicochemical parameters. In the present study, we expanded the library of ITD congeners and evaluated their receptor-binding affinity using intact Sf-9 cells. The QSAR analysis for the expanded set revealed the significance of the third physicochemical parameter, the negative steric effect for long substituents. We also evaluated the larvicidal activity of the synthesized compounds against Spodoptera litura; however, it was not correlated to the binding affinity. The results obtained here suggests that the pharmacokinetic properties must be improved to enhance the larvicidal activity of ITDs.     

Evaluating the Relationship Between Variance in Enzyme Expression and Toxicant Concentration in Health Risk Assessment

The replacement of default uncertainty factors with those based on chemical-specific data is a topic of interest to a growing number of government-based organizations and those in affiliated professional societies. The division of the uncertainty factors for animal-to-human extrapolation and human interindividual variance (UF_A and UF_H, respectively) into their pharmacodynamic (PD) and pharmacokinetic (PK) components invites additional and specific considerations. Where data are available, or substantiated PK models have been developed, the animal-to-human chemical-specific differences have been quantified and utilized to replace the PK component of the uncertainty factor. The increasing degree to which the genome is being characterized has stimulated additional interest in describing the impact of genetic polymorphisms on susceptibility. Frequently, proteins for which the genes are being evaluated are the group of xenobiotic metabolizing enzymes. In-depth understanding of the genetic polymorphisms of genes coding for Aldehyde dehydrogenase, glucuronyl transferase and cytochrome P450 enzyme forms has been combined with information on the bioactivation or detoxication of environmental contaminants. The preliminary conclusion of some of these considerations is that alterations in enzyme content or enzyme activity result in a de facto alteration of risk. While this may be true of the “all-or-none” genetic alterations, the impact of more subtle changes in enzyme content and/or activity are more difficult to predict. The hepatotoxicity of trichloroethylene (TCE) is dependent upon an initial, cytochrome P450 2E1 (CYP2E1)-mediated oxidative step. Variance of CYP2E1 content of human liver has been characterized from a bank of tissues from human organ donors and combined with data describing the in vitro Michaelis-Menten kinetic parameters in order to extrapolate the metabolic capacity (and variance thereof) from in vitro to in vivo and assess its impact on PK through incorporation in a physiologically based pharmacokinetic (PBPK) model. This presentation summarizes that work, and demonstrates and discusses why extremes of CYP2E1-mediated metabolic capacity in adult humans has virtually no impact on the PK metric most closely related to hepatotoxic injury from TCE exposure.     

Mathematical modeling of pulmonary tuberculosis therapy: Insights from a prototype model with rifampin

There is a critical need for improved and shorter tuberculosis (TB) treatment. Current in vitro models of TB, while valuable, are poor predictors of the antibacterial effect of drugs in vivo. Mathematical models may be useful to overcome the limitations of traditional approaches in TB research. The objective of this study was to set up a prototype mathematical model of TB treatment by rifampin, based on pharmacokinetic, pharmacodynamic and disease submodels.The full mathematical model can simulate the time-course of tuberculous disease from the first day of infection to the last day of therapy. Therapeutic simulations were performed with the full model to study the antibacterial effect of various dosage regimens of rifampin in lungs.The model reproduced some qualitative and quantitative properties of the bactericidal activity of rifampin observed in clinical data. The kill curves simulated with the model showed a typical biphasic decline in the number of extracellular bacteria consistent with observations in TB patients. Simulations performed with more simple pharmacokinetic/pharmacodynamic models indicated a possible role of a protected intracellular bacterial compartment in such a biphasic decline.This modeling effort strongly suggests that current dosage regimens of RIF may be further optimized. In addition, it suggests a new hypothesis for bacterial persistence during TB treatment.     

Optimization of ketone-based P2Y12 receptor antagonists as antithrombotic agents: Pharmacodynamics and receptor kinetics considerations

Modification of a series of P2Y₁₂ receptor antagonists by replacement of the ester functionality was aimed at minimizing the risk of in vivo metabolic instability and pharmacokinetic variability. The resulting ketones were then optimized for their P2Y₁₂ antagonistic and anticoagulation effects in combination with their physicochemical and absorption profiles. The most promising compound showed very potent antiplatelet action in vivo. However, pharmacodynamic–pharmacokinetic analysis did not reveal a significant separation between its anti-platelet and bleeding effects. The relevance of receptor binding kinetics to the in vivo profile is described.     

Evaluating adsorbed-phase activity coefficient models using a 2D-lattice model

Despite the wide use of the real adsorbed solution theory to predict multicomponent adsorption equilibrium, the models used for the adsorbed phase activity coefficients are usually borrowed from the gas–liquid phase equilibria. In this work, the accuracy of the Wilson and NRTL models for evaluating adsorbed phase activity coefficients is tested using a 2D-lattice model. An accurate model for adsorbed-phase activity coefficients should have no problem in fitting adsorption data obtained using this simple lattice model. The results, however, show that the commonly used Wilson and NRTL models cannot describe the adsorbed phase activity coefficients for slightly non-ideal to strong non-ideal mixtures. Therefore, until new models for adsorbed phase activity coefficients are developed, we should use existing models for liquids with care. In the second part of this work, the use of Monte Carlo simulations on a segregated 2D-lattice model, for predicting adsorption of mixtures is investigated. The segregated model assumes that the competition for adsorption occurs at isolated adsorption sites, and that the molecules from each adsorption site interact with the bulk phase independently. Two binary mixtures in two adsorbent materials were used as case studies for testing the predictions of the segregated 2D-lattice model: the binary system CO₂–N₂ in the hypothetical pure silica zeolite PCOD8200029, with isolated adsorption sites and normal preference for adsorption, and the binary system CO₂–C₃H₈ in pure silica mordenite (MOR), with isolated adsorption sites and inverse site preference. The segregated 2D-lattice model provides accurate predictions for the system CO₂–N₂ in PCOD8200029 but fails in predicting the adsorption behaviour of CO₂–C₃H₈ in pure silica MOR. The predictions of the segregated ideal adsorbed solution theory model are superior to those of the 2D-lattice model.     

Synthesis and evaluation of antitubercular activity of fluorinated 5-aryl-4-(hetero)aryl substituted pyrimidines

Various 5-(fluoroaryl)-4-(hetero)aryl substituted pyrimidines have been synthesized based on the Suzuki cross-coupling and nucleophilic aromatic substitution of hydrogen (S_N^H) reactions starting from commercially available 5-bromopyrimidine and their antitubercular activity against Mycobacterium tuberculosis H₃₇Rv has been explored. The outcome of the study disclose that, some of the compounds have showed promising activity in micromolar concentration against Mycobacterium tuberculosis H₃₇Rv, Mycobacterium avium, Mycobacterium terrae, and multidrug-resistant strains isolated from tuberculosis patients in Ural region (Russia). The data concerning the ‘structure–activity’ relationship for fluorinated compounds have been discussed.     

Discovery of 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)-5-tert-butyl-1,3,4-thiadiazole (GCC2680) as a potent,selective and orally efficacious cannabinoid-1 receptor antagonist

Structure–activity relationship studies in a series of diarylpyrazolyl thiadiazoles identified cannabinoid-1 receptor antagonists with excellent potency and selectivity. Based on its exceptional in vivo efficacy in animal models and its favorable pharmacokinetic and toxicological profiles, 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)-5-tert-butyl-1,3,4-thiadiazole (GCC2680) was selected as a preclinical candidate for the treatment of obesity.     

Optimizing bioavailability of oral administration of small peptides through pharmacokinetic and pharmacodynamic parameters: The effect of water and timing of meal intake on oral delivery of Salmon Calcitonin

Background

To investigate the influence of water intake and dose timing on the pharmacokinetic and pharmacodynamic parameters of an oral formulation of salmon calcitonin (sCT).

Methods

The study was a randomized, partially-blind, placebo-controlled, single dose, exploratory crossover phase I study. 56 healthy postmenopausal women were randomly assigned to receive five treatments. The treatments comprised a combination of study medication (SMC021 (0.8 mg sCT + 200 mg 5-CNAC), SMC021 placebo, or 200 IU Miacalcic^® NS nasal spray), water volume given with the tablet (50 or 200 ml water), and time between dosing and meal (10, 30, or 60 minutes pre-meal). Plasma sCT levels and changes in the bone resorption (C-terminal telopeptide of collagen type I) was investigated. Trial regristration

Results

Oral delivery of 0.8 mg of sCT with 50 ml of water compared to that with 200 ml water resulted in a two-fold increase in maximum concentration (C_max and AUC_0–4) of plasma sCT but comparable time to reach maximum concentration (T_max). The sCT AUC_0–4 with 50 ml of water was 4-fold higher than that obtained with nasal calcitonin. The increased absorption of sCT resulted in increased efficacy demonstrated by AUC of the relative change of serum CTX-I measured in the 6 hours post dosing.

Conclusion

0.8 mg sCT with 50 ml of water taken 30 and 60 minutes prior to meal time resulted in optimal pharmacodynamic and pharmacokinetic parameters. The data suggest that this novel oral formulation may have improved absorption and reduction of bone resorption compared to that of the nasal form.     

Structure activity relationship studies of 3-arylsulfonyl-pyrido[1,2-a]pyrimidin-4-imines as potent 5-HT6 antagonists

Comprehensive structure activity relationship (SAR) studies were conducted on a focused screening hit, 2-(methylthio)-3-(phenylsulfonyl)-4H-pyrido[1,2-a]pyrimidin-4-imine (1, IC₅₀: 4.0 nM), as 5-HT₆ selective antagonists. Activity was improved some 2–4 fold when small, electron-donating groups were added to the central core as observed in 19, 20 and 26. Molecular docking of key compounds in a homology model of the human 5-HT₆ receptor was used to rationalize our structure–activity relationship (SAR) findings. In pharmacokinetic experiments, compound 1 displayed good brain uptake in rats following intra-peritoneal administration, but limited oral bioavailability.     

3D-QSAR and QSSR studies of 3,8-diazabicyclo[4.2.0]octane derivatives as neuronal nicotinic acetylcholine receptors by comparative molecular field analysis (CoMFA)

High subtype selectivity (α4β2 over α2β3) of neuronal nicotinic acetylcholine receptor (nAChR) agonists is critical for the rational design of less toxic drugs used for the treatment of neurodegenerative and psychiatric diseases. Here, three CoMFA models of pEC₅₀(α4β2), pEC₅₀(α2β3) and p[EC₅₀(α4β2)/EC₅₀(α2β3)] (pEC₅₀(α4β2)pEC₅₀(α2β3)) were developed to study the quantitative structure–activity relationship (QSAR) and quantitative structure–selectivity relationship (QSSR) of the 3,8-diazabicyclo[4.2.0]octane derivatives as nAChRs agonists. The parameters of the three models were 0.584, 0.792, and 0.599 for cross-validated r² (r²_CV), 0.924, 0.935 and 0.875 for conventional r². Analyses indicated that both the steric and electrostatic factors should be considered in the rational design of more active and selective nAChR agonists.     

Mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide

The thioredoxin system, which consists of a family of proteins, including thioredoxin (Trx), peroxiredoxin (Prx), and thioredoxin reductase (TrxR), plays a critical role in the defense against oxidative stress by removing harmful hydrogen peroxide (H₂O₂). Specifically, Trx donates electrons to Prx to remove H₂O₂ and then TrxR maintains the reduced Trx concentration with NADPH as the cofactor. Despite a great deal of kinetic information gathered on the removal of H₂O₂ by the Trx system from various sources/species, a mechanistic understanding of the associated enzymes is still not available. We address this issue by developing a thermodynamically consistent mathematical model of the Trx system which entails mechanistic details and provides quantitative insights into the kinetics of the TrxR and Prx enzymes. Consistent with experimental studies, the model analyses of the available data show that both enzymes operate by a ping-pong mechanism. The proposed mechanism for TrxR, which incorporates substrate inhibition by NADPH and intermediate protonation states, well describes the available data and accurately predicts the bell-shaped behavior of the effect of pH on the TrxR activity. Most importantly, the model also predicts the inhibitory effects of the reaction products (NADP⁺ and Trx(SH)₂) on the TrxR activity for which suitable experimental data are not available. The model analyses of the available data on the kinetics of Prx from mammalian sources reveal that Prx operates at very low H₂O₂ concentrations compared to their human parasite counterparts. Furthermore, the model is able to predict the dynamic overoxidation of Prx at high H₂O₂ concentrations, consistent with the available data. The integrated Prx–TrxR model simulations well describe the NADPH and H₂O₂ degradation dynamics and also show that the coupling of TrxR- and Prx-dependent reduction of H₂O₂ allowed ultrasensitive changes in the Trx concentration in response to changes in the TrxR concentration at high Prx concentrations. Thus, the model of this sort is very useful for integration into computational H₂O₂ degradation models to identify its role in physiological and pathophysiological functions.