Species Differences in Metabolism of Soluble Epoxide Hydrolase Inhibitor,EC1728, Highlight the Importance of Clinically Relevant Screening Mechanisms in Drug Development

There are few novel therapeutic options available for companion animals, and medications rely heavily on repurposed drugs developed for other species. Considering the diversity of species and breeds in companion animal medicine, comprehensive PK exposures in the companion animal patient is often lacking. The purpose of this paper was to assess the pharmacokinetics after oral and intravenous dosing in domesticated animal species (dogs, cats, and horses) of a novel soluble epoxide hydrolase inhibitor, EC1728, being developed for the treatment of pain in animals. Results: Intravenous and oral administration revealed that bioavailability was similar for dogs, and horses (42 and 50% F) but lower in mice and cats (34 and 8%, respectively). Additionally, clearance was similar between cats and mice, but >2× faster in cats vs. dogs and horses. Efficacy with EC1728 has been demonstrated in mice, dogs, and horses, and despite the rapid clearance of EC1728 in cats, analgesic efficacy was demonstrated in an acute pain model after intravenous but not oral dosing. Conclusion: These results demonstrate that exposures across species can vary, and investigation of therapeutic exposures in target species is needed to provide adequate care that addresses efficacy and avoids toxicity.     

Network formation and photoluminescence in copper(i) halide complexes with substituted piperazine ligands

The synthesis, X-ray structures and photophysics of ten complexes of CuX (X = I or Br) with bridging N-substituted and N,N'-disubstituted piperazines (Pip) are presented. Depending on the steric demand of the Pip substituents, the complexes fall into four categories: (CuX)(4)(Pip)(2), which are networks of linked Cu(4)X(4) cubane units, (CuX)(2)(Pip), which are chains of linked Cu(2)X(2) rhombs, and (CuX)(2)(Pip)(2) or (CuX)(4)(Pip)(4), which are simple rhomboid dimers and cubane tetramers. A combination of spectroscopic studies and DFT calculations was used to investigate the luminescence of the products. The results suggest that the relatively high energy emission seen in dimers is due to cluster-centred (XMLT/metal-centred) excitations for the aliphatic amines and MLCT (d →π*) for aromatic amines, and low energy emission seen in the tetramers is the result of cluster-centred transitions. The (CuI)(2)(Pip) complexes act as sensor materials, undergoing irreversible reaction with aliphatic and aromatic amines (Nu) in the vapour state, irreversibly producing cubanes (CuI)(4)Nu(4), with corresponding production of long wavelength emission.     

Discriminant analysis in the presence of interferences: Combined application of target factor analysis and a Bayesian soft-classifier

A method is described for performing discriminant analysis in the presence of interfering background signal. The method is based on performing target factor analysis on a data set comprised of contributions from analyte(s) and interfering components. A library of data from representative analyte classes is tested for possible contributing factors by performing oblique rotations of the principal factors to obtain the best match, in a least-squares sense, between test and predicted vectors. The degree of match between the test and predicted vectors is measured by the Pearson correlation coefficient, r, and the distribution of r for each class is determined. A Bayesian soft classifier is used to calculate the posterior probability based on the distributions of r for each class, which assist the analyst in assessing the presence of one or more analytes. The method is demonstrated by analyses performed on spectra obtained by laser induced breakdown spectroscopy (LIBS). Single and multiple bullet jacketing transfers to steel and porcelain substrates were analyzed to identify the jacketing materials. Additionally, the metal surrounding bullet holes was analyzed to identify the class of bullet jacketing that passed through a stainless steel plate. Of 36 single sample transfers, the copper jacketed (CJ) and non-jacketed (NJ) class on porcelain had an average posterior probability of the metal deposited on the substrate of 1.0. Metal jacketed (MJ) bullet transfers to steel and porcelain were not detected as successfully. Multiple transfers of CJ/NJ and CJ/MJ on the two substrates resulted in posterior probabilities that reflected the presence of both jacketing materials. The MJ/NJ transfers gave posterior probabilities that reflected the presence of the NJ material, but the MJ component was mistaken for CJ on steel, while non-zero probabilities were obtained for both CJ and MJ on porcelain. Jacketing transfer from a bullet to steel as the projectile passed through the steel also proved difficult to analyze. Over 50% of the samples left insufficient transfer to be identified. Transfer from NJ and CJ jacketing was successfully identified by posterior probabilities greater than 0.8.     

Portrait of a Family of Highly Stabilizing and Selective Guanine Quadruplex Platinum(II)-Based Binders

The long-standing history of platinum coordination complexes in nucleic acid recognition attests to the unique suitability of such species for therapeutic applications. Here, we report the synthetic exploration and development of a family of di-imine ligands, and their platinum(II) complexes, elaborated on a 3-(2-pyridyl)-[1,2,4]triazolo[4,3-a]pyridine platform which, in its unsubstituted form, has recently been shown to display exceptional capabilities for guanine quadruplex (G4) targeting. The identification of facile, high-yielding synthetic methods for the derivatization of this platform for the incorporation of additional sites of interactions with guanine quadruplex loops and grooves, along with the optimization of platinum(II) complexation methods, are discussed. Gratifyingly, preliminary biophysical screening of this novel family of binders validates all but one family members as robust G4 binders and highlights enhanced selectivity for quadruplex versus duplex DNA compared to the parent compound. These results bear promise for practical developments based on this platform.     

DEB-FAPy-dG Adducts of 1,3-Butadiene: Synthesis,Structural Characterization,and Formation in 1,2,3,4-Diepoxybutane Treated DNA**

Metabolic activation of the human carcinogen 1,3-butadiene (BD) by cytochrome 450 monooxygenases gives rise to a genotoxic diepoxide, 1,2,3,4-diepoxybutane (DEB). This reactive electrophile alkylates guanine bases in DNA to produce N7-(2-hydroxy-3,4-epoxy-1-yl)-dG (N7-DE-dG) adducts. Because of the positive charge at the N7 position of the purine heterocycle, N7-DEB-dG adducts are inherently unstable and can undergo spontaneous depurination or base-catalyzed imidazole ring opening to give N⁶-[2-deoxy-D-erythro-pentofuranosyl]-2,6-diamino-3,4-dihydro-4-oxo-5-N-1-(oxiran-2-yl)propan-1-ol-formamidopyrimidine (DEB-FAPy-dG) adducts. Here we report the first synthesis and structural characterization of DEB-FAPy-dG adducts. Authentic standards of DEB-FAPy-dG and its ¹⁵N₃-labeled analogue were used for the development of a quantitative nanoLC-ESI⁺-HRMS/MS method, allowing for adduct detection in DEB-treated calf thymus DNA. DEB-FAPy-dG formation in DNA was dependent on DEB concentration and pH, with higher numbers observed under alkaline conditions.     

Using water–solvent systems to estimate in vivo blood–tissue partition coefficients

Background

Blood–tissue partition coefficients indicate how a chemical will distribute throughout the body and are an important part of any pharmacokinetic study. They can be used to assess potential toxicological effects from exposure to chemicals and the efficacy of potential novel drugs designed to target certain organs or the central nervous system. In vivo measurement of blood–tissue partition coefficients is often complicated, time-consuming, and relatively expensive, so developing in vitro systems that approximate in vivo ones is desirable. We have determined such systems for tissues such as brain, muscle, liver, lung, kidney, heart, skin, and fat.

Results

Several good (p < 0.05) blood–tissue partition coefficient models were developed using a single water–solvent system. These include blood–brain, blood–lung, blood–heart, blood–fat, blood–skin, water–skin, and skin permeation. Many of these partition coefficients have multiple water–solvent systems that can be used as models. Several solvents—methylcyclohexane, 1,9-decadiene, and 2,2,2-trifluoroethanol—were common to multiple models and thus a single measurement can be used to estimate multiple blood–tissue partition coefficients. A few blood–tissue systems require a combination of two water–solvent partition coefficient measurements to model well (p < 0.01), namely: blood–muscle: chloroform and dibutyl ether, blood–liver: N-methyl-2-piperidone and ethanol/water (60:40) volume, and blood–kidney: DMSO and ethanol/water (20:80) volume.

Conclusion

In vivo blood–tissue partition coefficients can be easily estimated through water–solvent partition coefficient measurements.

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Graphical abstract: Predicted blood-brain barrier partition coefficients coloured by measured log BB value

     

Comparative analysis of automotive paints by laser induced breakdown spectroscopy and nonparametric permutation tests

Laser-induced breakdown spectroscopy (LIBS) has been investigated for the discrimination of automobile paint samples. Paint samples from automobiles of different makes, models, and years were collected and separated into sets based on the color, presence or absence of effect pigments and the number of paint layers. Twelve LIBS spectra were obtained for each paint sample, each an average of a five single shot “drill down” spectra from consecutive laser ablations in the same spot on the sample. Analyses by a nonparametric permutation test and a parametric Wald test were performed to determine the extent of discrimination within each set of paint samples. The discrimination power and Type I error were assessed for each data analysis method. Conversion of the spectral intensity to a log-scale (base 10) resulted in a higher overall discrimination power while observing the same significance level. Working on the log-scale, the nonparametric permutation tests gave an overall 89.83% discrimination power with a size of Type I error being 4.44% at the nominal significance level of 5%. White paint samples, as a group, were the most difficult to differentiate with the power being only 86.56% followed by 95.83% for black paint samples. Parametric analysis of the data set produced lower discrimination (85.17%) with 3.33% Type I errors, which is not recommended for both theoretical and practical considerations. The nonparametric testing method is applicable across many analytical comparisons, with the specific application described here being the pairwise comparison of automotive paint samples.     

Non‐parametric permutation test for the discrimination of float glass samples based on LIBS spectra

Laser‐induced breakdown spectroscopy (LIBS) coupled with non‐parametric permutation based hypothesis testing is demonstrated to have good performance in discriminating float glass samples. This type of pairwise sample comparison is important in manufacturing process quality control, forensic science and other applications where determination of a match probability between two samples is required. Analysis of the pairwise comparisons between multiple LIBS spectra from a single glass sample shows that some assumptions required by parametric methods may not hold in practice, motivating the adoption of a non‐parametric permutation test. Without rigid distributional assumptions, the permutation test exhibits excellent discriminating power while holding the actual size of Type I error at the nominal level. Copyright © 2010 John Wiley & Sons, Ltd.     

Nickel-catalyzed asymmetric reductive cross-coupling of α-chloroesters with (hetero)aryl iodides

An asymmetric reductive cross-coupling of α-chloroesters and (hetero)aryl iodides is reported. This nickel-catalyzed reaction proceeds with a chiral BiOX ligand under mild conditions, affording α-arylesters in good yields and enantioselectivities. The reaction is tolerant of a variety of functional groups, and the resulting products can be converted to pharmaceutically-relevant chiral building blocks. A multivariate linear regression model was developed to quantitatively relate the influence of the α-chloroester substrate and ligand on enantioselectivity.

A Ni-catalyzed enantioselective reductive cross-coupling of α-chloroesters and (hetero)aryl iodides is reported. A MLR model was developed to quantitatively relate the influence of the α-chloroester substrate and ligand on enantioselectivity.     

Structural Analysis of Bisphenol-A and its Methylene,Sulfur, and Oxygen Bridged Bisphenol Analogs

The molecular structures of bisphenol-A, C(CH₃)₂(p-C₆H₄OH)₂ (monoclinic, P2₁/n, a = 11.1940(6) Å, b = 18.738(1) Å, c = 17.8623(9) Å, β = 100.571(1)°), its methylene (CH₂) and heteroatom (S, O) bridged analogs, CH₂(p-C₆H₄OH)₂ (monoclinic, P2₁/n, a = 5.4351(1) Å, b = 20.7895(3) Å, c = 8.8432(1) Å, β = 93.419(1)°), S(p-C₆H₄OH)₂ (monoclinic, P2₁/n, a = 5.5115(1) Å, b = 21.0666(2) Å, c = 8.6917(1) Å, β = 92.962(1)°) and O(p-C₆H₄OH)₂ (orthorhombic, Pbcn, a = 5.2745(5) Å, b = 8.2724(8) Å, c = 22.085(2) Å), have been determined by X-ray diffraction at 115 K, revealing structural differences in the series of compounds. The results show that the C_aryl–X_bridge–C_aryl angles (X_bridge = C(CH₃)₂, CH₂, S, O) span a range greater than 14°. The dihedral angle between the planes of the hydroxyphenyl groups also varies according to the identity of the bridging group, varying from 67.24(2)° in S(p-C₆H₄OH)₂ to 85.82(4)° in C(CH₃)₂(p-C₆H₄OH)₂. In addition, the pitch angle, which more accurately describes the propeller-like nature of these bisphenolic compounds, varies from 39.88(3)° in S(p-C₆H₄OH)₂ to 59.62(7)° in C(CH₃)₂(p-C₆H₄OH)₂. Ab initio electronic structure calculations predict very similar bond lengths and angles to those observed crystallographically; however, the predicted dihedral angles and pitch angles are quite different, suggesting that these features are greatly influenced by crystal packing.