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Diverse Compounds (diverse + compound)
Selected AbstractsNovel estrogen receptor ligands and their structure,activity relationship evaluated by scintillation proximity assay for high-throughput screeningDRUG DEVELOPMENT RESEARCH, Issue 4 2005Ling He Abstract The estrogen receptor (ER) is an important drug target with allosteric characteristics that binds orthotopic hormones and other ligands. A recently developed scintillation proximity (SPA)-based assay for high-throughput screening (HTS) of compound libraries was used to identify novel estrogen receptor ligands that might have ER subtype selective binding activity. Radioligand binding was determined in a multi-detector scintillation counter designed for microtitration plates. Equilibrium binding experiments and kinetic competition tests were performed with [3H]-estradiol and human ER, and ER, receptors. A library of 6,000 structurally diverse compounds was screened. From this, several novel ligands were identified that showed pronounced subtype-selective differences in ligand binding for ER, and ER,. The observed equilibrium dissociation constant (Kd) for the binding of [3H]estradiol to ER, and ER, receptors were approximately 0.25 and 0.64 nM, respectively. When 17,-estradiol, raloxifene and daidzein were tested for binding affinity to ER, in a competition assay, the IC50 values were 0.34, 1.31, and 75.6 nM, respectively. When tested for binding affinity to ER,, the IC50 values were 1.05, 11.4, and 10.6 nM, respectively. The results obtained show that the methodology is valid in comparison to previously published data regarding estradiol and other standard compounds (raloxifene and daidzein) binding characteristics of estrogen receptors. The assay is also well suited to applied research as a tool in HTS of compound libraries in the search of ER ligands. Several novel active compounds were identified and selected as potent ER subtype ligands. Drug Dev Res 64:203,212, 2005. © 2005 Wiley-Liss, Inc. [source] Rapidly profiling blood,brain barrier penetration with liposome EKCELECTROPHORESIS, Issue 14 2007Yongjun Wang Abstract This report intended to study the potential of liposome EKC (LEKC) as a convenient and high-throughput screening tool to assess drug penetration across the blood,brain barrier (BBB). The retention factors (k) of 24 structurally diverse compounds were determined with LEKC and vesicle EKC (VEKC), respectively. Principal component analysis of the steady-state concentrations ratio of compounds in the brain and in the blood expressed as log,BB, log,kLEKC, log,kVEKC, and other lipophilic descriptors including octanol/water partition coefficient (Clog,P), octanol/water distribution coefficients (log,D7.4), and polar surface area (PSA), showed the maximum similarity of partitioning processes in LEKC to drug penetration across the BBB. Furthermore, the log,BB were correlated with the above five lipophilic descriptors, and the results showed that log,kLEKC gave the better correlation coefficient (r2,=,0.811, p <0.0001) than those of log,D7.4, Clog,P, PSA, and log,kVEKC (r2,=,0.730, 0.672, 0.627, and 0.620, p <0.0001). This is the first report of the use of LEKC as a promising rapid tool to profile drug penetration across the BBB. [source] Development of Pharmaceutical Drugs, Drug Intermediates and Ingredients by Using Direct Organo-Click ReactionsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 6 2008Dhevalapally B. Ramachary Abstract Here we report on our studies of the use of combinations of amino acids, amines, K2CO3 or Cs2CO3 and CuSO4/Cu for catalysing green cascade reactions. We aimed to prepare the highly reactive and substituted olefin species 7 and 8, under very mild and environmentally friendly conditions, thus giving the hydrogenated products 10 and 12 through the action of Hantzsch ester (4) by self-catalysis through decreasing the HOMO,LUMO energy gaps between olefins 7/8 and Hantzsch ester (4) through biomimetic reductions. Highly useful compounds 10 to 14 were assembled from simple substrates such as aldehydes 1, ketones 2, CH acids 3, Hantzsch ester (4) and alkyl halides 5 by diversity-oriented green synthesis involving cascade olefination/hydrogenation (O/H), olefination/hydrogenation/alkylation (O/H/A) and hydrogenation/olefination/hydrogenation (H/O/H) reaction sequences in one-pot fashion with stereospecific organo- and organo-/metal-carbonate catalysis. Highly functionalized diverse compounds such as 10 to 14 are biologically active products and have found wide applications as pharmaceutical drugs, drug intermediates and drug ingredients. For the first time in organocatalysis, we report the O/H/A/TE reaction to furnish high yields of transesterification products 11 by simply mixing the reactants under proline/K2CO3 catalysis conditions. Additionally, a novel organocatalytic H/O/H reaction sequence for the synthesis of alkyl-substituted aromatics has been developed. Furthermore, for the first time we have developed organocatalysed cascade olefination/hydrogenation/hydrolysis (O/H/H) reactions to furnish highly useful materials such as 2-oxochroman-3-carboxylic acid (14kc) and 2-amino-4H -chromene-3-carbonitrile (14kj) in good yields. Experimentally simple and environmentally friendly organocatalytic two-carbon homologation through cascade O/H/H reactions of aldehydes 1, Meldrum's acid (3c), Hantzsch ester (4) and acetic acid/triethylamine in ethanol has been demonstrated. Additionally, we have developed a green synthesis of the highly substituted 1,2,3-triazole 17 from simple substrates through a two-step combination of olefination/hydrogenation/alkylation and Huisgen cycloaddition reaction sequences under stereospecific organocopper catalysis conditions. In this paper we have found strong support for our hypothesis that, "decreasing the HOMO,LUMO energy gap between olefins 7/8 and Hantzsch ester (4) will drive the biomimetic hydrogenation reaction by self-catalysis". This self-catalysis was further confirmed with many varieties of examples.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) [source] Measurement of dissociation constants (pKa values) of organic compounds by multiplexed capillary electrophoresis using aqueous and cosolvent buffers,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2008Marina Shalaeva Abstract Evaluation of a multiplexed capillary electrophoresis (CE) method for pKa measurements of organic compounds, including low solubility compounds, is presented. The method is validated on a set of 105 diverse compounds, mostly drugs, and results are compared to literature values obtained from multiple references. Two versions of the instrument in two different labs were used to collect data over a period of 3 years and inter-laboratory and inter-instrument variations are discussed. Twenty-four point aqueous and mixed cosolvent buffer systems were employed to improve the accuracy of pKa measurements. It has been demonstrated that the method allows direct pKa measurements in aqueous buffers for many compounds of low solubility, often unattainable by other methods. The pKa measurements of compounds with extremely low solubility using multiplexed CE with methanol/water cosolvent buffers are presented. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:2581,2606, 2008 [source] QSAR analysis of interstudy variable skin permeability based on the "latent membrane permeability" conceptJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2003Shin-Ichi Fujiwara Abstract A number of QSAR models for skin permeability have been proposed, but these models lack consistency due to interspecies and interlaboratory differences. This study was initiated to extract an essential QSAR from the multiplicity of data sets of skin permeability by using a novel statistical approach. Ten data sets were collected from the literature, which include a total of 111 permeability coefficients in human, hairless mouse, or hairless rat skin for 94 structurally diverse compounds. Following a Potts and Guy's approach, the octanol/water partition coefficient and molecular weight were chosen as molecular descriptors. All of the data sets were analyzed simultaneously, assuming that all of the sets share a latent, common factor as far as the structure/permeability relationship is concerned. Despite the fact that the degree-of-freedom for the present analysis was limited compared with that for individual regression analyses, the determination coefficients (R2) were high enough for all the 10 data sets, with an average R2 of 0.815 (average R2,=,0.825 for individual analyses). Thus, skin permeability of compounds can be well explained from the log P and M.W., where the ratio of the contribution to skin permeability was approximately 1:1. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1939,1946, 2003 [source] Design of Multi-Component Reactions: From Libraries of Compounds to Libraries of ReactionsMOLECULAR INFORMATICS, Issue 5-6 2006Maxim Abstract Multi-Component Reactions (MCRs) constitute a methodology to shorter syntheses of natural products or complex molecules similar to natural. Due to the large number of accessible compounds and other advantages, this type of chemistry has become very popular in the community of combinatorial chemists. In the last 5 years combinatorial chemistry is has evolved from the synthesis of libraries based on one scaffold to the synthesis of structurally diverse compounds, better known as diversity-oriented synthesis. Following this trend, the design of MCRs is becoming a tool kit for chemists to explore chemistry space broadly with complex and diverse structures. Various approaches to the creation of novel MCRs including "union of MCRs", "substrate design", and "reaction operator" are discussed here. [source] Insight into the Bioactivity and Metabolism of Human Glucagon Receptor Antagonists from 3D-QSAR AnalysesMOLECULAR INFORMATICS, Issue 8 2004HaiFeng Chen Abstract Descriptors, such as logP, the number of hydrogen bond donors, the number of hydrogen bond acceptors, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) combined with fields of CoMFA and CoMSIA to construct models for hyperglycemia decrease activity and metabolism of human glucagon receptor antagonists. The results reveal that including logP, HOMO and LUMO energies is meaningful for QSAR/QSMR model. The models were validated by using a test set of structural diverse compounds that had not been included in the CoMFA and CoMSIA models. Support Vector Machines (SVM) have been used to select the suitable additional descriptors to construct 3D-QSAR/QSMR models. A key factor to mention is that activity and metabolism models simultaneously. These in silico ADME models are helpful in making quantitative prediction of inhibitory activities and rates of metabolism before resorting in vitro and in vivo experimentation. [source] Molecular Connectivity: Polarity Correction to Improve Correlation with HydrophobicityMOLECULAR INFORMATICS, Issue 2-3 2004Abstract Contrary to belief in some quarters, molecular connectivites correlate only very poorly with hydrophobicity. We have devised a simple polarity correction to the calculation of first-order molecular connectivity (1,), which involves subtracting, instead of adding, the bond contributions (, values) for bonds between atoms i and j where j is a heteroatom other than halogen, to give a 1,p value. For a set of 23 diverse substituents, the correlation between 1, and , (the hydrophobic substituent constant) yielded r2=0.123, whilst that between 1,p and , yielded r2=0.771. When the method was applied to the correlation of the protein-binding constants for a set of 42 diverse compounds with 1,, r2 improved from 0.078 to 0.443., [source] Direct metabolic fingerprinting of commercial herbal tinctures by nuclear magnetic resonance spectroscopy and mass spectrometry,PHYTOCHEMICAL ANALYSIS, Issue 4 2009Matteo Politi Abstract Introduction Tinctures are widely used liquid pharmaceutical preparations traditionally obtained by maceration of one or more medicinal plants in ethanol,water solutions. Such a process results in the extraction of virtually hundreds of structurally diverse compounds with different polarities. Owing to the large chemical diversity of the constituents present in the herbal tinctures, the analytical tools used for the quality control of tinctures are usually optimised only for the detection of single chemical entities or specific class of compounds. Objective In order to overcome the major limitations of the current methods used for analysis of tinctures, a new methodological approach based on NMR spectroscopy and MS spectrometry has been tested with different commercial tinctures. Methodology Diffusion-edited 1H-NMR (1D DOSY) and 1H-NMR with suppression of the ethanol and water signals have been applied here for the first time to the direct analysis of commercial herbal tinctures derived from Echinacea purpurea, Hypericum perforatum, Ginkgo biloba and Valeriana officinalis. The direct injection of the tinctures in the MS detector in order to obtain the corresponding metabolic profiles was also performed. Results Using both NMR and MS methods it was possible, without evaporation or separation steps, to obtain a metabolic fingerprint able to distinguish between tinctures prepared with different plants. Batch-to-batch homogeneity, as well as degradation after the expiry date of a batch, was also investigated. Conclusion The techniques proposed here represent fast and convenient direct analyses of medicinal herbal tinctures. Copyright © 2009 John Wiley & Sons, Ltd. [source] Probing nonnucleoside inhibitor-induced active-site distortion in HIV-1 reverse transcriptase by transient kinetic analysesPROTEIN SCIENCE, Issue 8 2007Qing Xia Abstract Nonnucleoside reverse transcriptase inhibitors (NNRTI) are a group of structurally diverse compounds that bind to a single site in HIV-1 reverse transcriptase (RT), termed the NNRTI-binding pocket (NNRTI-BP). NNRTI binding to RT induces conformational changes in the enzyme that affect key elements of the polymerase active site and also the association between the two protein subunits. To determine which conformational changes contribute to the mechanism of inhibition of HIV-1 reverse transcription, we used transient kinetic analyses to probe the catalytic events that occur directly at the enzyme's polymerase active site when the NNRTI-BP was occupied by nevirapine, efavirenz, or delavirdine. Our results demonstrate that all NNRTI,RT,template/primer (NNRTI,RT,T/P) complexes displayed a metal-dependent increase in dNTP binding affinity (Kd) and a metal-independent decrease in the maximum rate of dNTP incorporation (kpol). The magnitude of the decrease in kpol was dependent on the NNRTI used in the assay: Efavirenz caused the largest decrease followed by delavirdine and then nevirapine. Analyses that were designed to probe direct effects on phosphodiester bond formation suggested that the NNRTI mediate their effects on the chemistry step of the DNA polymerization reaction via an indirect manner. Because each of the NNRTI analyzed in this study exerted largely similar phenotypic effects on single nucleotide addition reactions, whereas each of them are known to exert differential effects on RT dimerization, we conclude that the NNRTI effects on subunit association do not directly contribute to the kinetic mechanism of inhibition of DNA polymerization. [source] SYMPOSIUM REVIEW: Revealing the structural basis of action of hERG potassium channel activators and blockersTHE JOURNAL OF PHYSIOLOGY, Issue 17 2010Matthew Perry Human ether-á-go-go related gene (hERG) potassium (K+) channels play a critical role in cardiac action potential repolarization. This is due, in large part, to the unique gating properties of these channels, which are characterized by relatively slow activation and an unusually fast and voltage-dependent inactivation. A large number of structurally diverse compounds bind to hERG and carry an unacceptably high risk of causing arrhythmias. On the other hand, drugs that increase hERG current may, at least in principle, prove useful for treatment of long QT syndrome. A few blockers have been shown to increase hERG current at potentials close to the threshold for channel activation , a process referred to as facilitation. More recently, a novel group of hERG channel activators have been identified that slow deactivation and/or attenuate inactivation. Structural determinants for the action of two different types of activators have been identified. These compounds bind at sites that are distinct from each other and also separate from the binding site of high affinity blockers. They reveal not only novel ways of chemically manipulating hERG channel function, but also interactions between structural domains that are critical to normal activation and inactivation gating. [source] | |||||||||||||