ADME Research Papers - Academia.edu (original) (raw)

S 5 4 1 3 5 9 -6 4 4 6 1 0 1 4 -see front matter

- by
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- Drug Discovery, Prediction Model, IDEA, ADME

Keywords: hAChE hBuChE Dual AChE inhibitors 6-Chloro-pyridonepezils In vitro blood brain barrier Molecular modeling ADME Alzheimer's disease a b s t r a c t 6-Chloro-pyridonepezils are chloropyridineedonepezil hybrids designed by combining the N-benzylpiperidine moiety present in donepezil with the 2-chloropyridine-3,5-dicarbonitrile heterocyclic ring system, both connected by an appropriate polymethylene linker. 6-Chloro-pyridonepezils 1e8 were prepared by reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile (13) [or 2,6-dichloropyridine-3,5-dicarbonitrile ] with suitable 2-(1-benzylpiperidin-4-yl)alkylamines (9e12). The biological evaluation showed that these new compounds are cholinesterase inhibitors, in the submicromolar range, one of them (6) being a potent hBuChE inhibitor (IC 50 ¼ 0.47 AE 0.08 mM). 6-Chloro-pyridonepezils 4, 7 and 8 are potent hAChE inhibitors showing IC 50 in the 0.013e0.054 mM range. Particularly, 6-chloro-pyridonepezil 8 is 625-fold more selective for hAChE than for hBuChE and compared to donepezil is equipotent for the inhibition of hAChE. Molecular modeling investigation on 6-chloro-pyridonepezils 4, 6e8 supports its dual AChE inhibitory profile, by binding simultaneously at the catalytic active and at peripheral anionic sites of the enzyme. The in vitro Blood Brain Barrier (BBB) and theoretical ADME analysis of 6-chloro-pyridonepezils 1e8 have been carried out. Overall, compound 8, is a permeable potent and selective dual AChEI that can be considered as a good candidate with potential impact for further pharmacological development in Alzheimer's therapy.

Objective: The objective of the study was to analyze the active principles of "Garam Masala" (routinely used spice-mix in Indian cuisine) for their antiinflammatory potential against Cyclooxygenase-2 (COX-2), a crucial player in inflammatory response in humans, using molecular docking simulation. Methods: After obtaining three-dimensional structures of spice phytochemicals and COX-2 protein from PUBCHEM and PDB databases, phytochemicals with suitable absorption, distribution, metabolism, and excretion (ADME) properties were docked against COX-2 protein using PyRx and AutoDock tools 1.5.6 and their binding properties were compared with "Coxibs" drugs (NSAIDs, known COX-2 inhibitors) to establish their anti-COX-2 potential. Results: Farnesiferol A showed better binding affinity to COX-2 whereas three other phytochemicals Piperine, Cedrelanol, and Usnic acid demonstrated comparable binding affinity like those of "coxibs." Conclusion: Molecular docking simulation and ADME analysis reveal that Farnesiferol A, Piperine, Cedrelanol, and Usnic acid could be considered for potential drug candidates for COX-2 inhibition due to their promising binding affinities with COX-2.

- by Saswata Dey
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- Phytochemical, Usnic Acid, AutoDock, ADME
- by Hartmut Derendorf
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- Pharmacokinetics, Pharmaceutical Sciences, Absorption, Bioavailability

Oral administration is the most desirable route of drug delivery for systemically active drugs. Oral drugs must possess a certain level of oral bioavailability, which is a product of oral absorption and first-pass effect. Low oral bioavailability may be attributed to poor absorption and/or high first-pass hepatic elimination. In the lead optimization stage of drug discovery, if the relative contribution of oral absorption and metabolism could be discerned for poorly bioavailable compounds, a path forward for remedy would be possible. This report describes an approach utilizing oral/intravenous pharmacokinetic data to estimate oral absorption. The fraction of dose absorbed is calculated as the ratio of the actual bioavailable fraction to the maximum bioavailable fraction estimated from systemic clearance. An arbitrary classification was devised where low absorption encompasses compounds whose extent of absorption is 20%, moderate is for those between 21% and 69%, and high is for those that show !70% absorption. There was approximately 78% concordance in rats, 65% in monkeys and almost complete concordance in dogs. This approach correctly identified the cause for low oral bioavailability for 11 out of 13 compounds evaluated, and therefore it could be used prospectively with nonradiolabeled compounds during the lead optimization process.

- by David Hesk
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- Drug Discovery, Pharmacokinetics, Dogs, Pharmaceutical Sciences

Inhibition of Rho kinase (ROCK) is an attractive strategy for the treatment of diseases such as hypertension, glaucoma, and cancer. Here we report chroman-3-amides as highly potent ROCK inhibitors with sufficient kinase selectivity, excellent cell activity, good microsomal stability, and desirable pharmacokinetic properties for study as potential therapeutic agents.

- by Thomas Bannister
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- Organic Chemistry, Modeling, Pharmacokinetics, Pharmaceutical Chemistry

There are currently about 10 000 drug-like compounds. These are sparsely, rather than uniformly, distributed through chemistry space. True diversity does not exist in experimental combinatorial chemistry screening libraries. Absorption, distribution, metabolism, and excretion (ADME) and chemical reactivity-related toxicity is low, while biological receptor activity is higher dimensional in chemistry space, and this is partly explainable by evolutionary pressures on ADME to deal with endobiotics and exobiotics. ADME is hard to predict for large data sets because current ADME experimental screens are multi-mechanisms, and predictions get worse as more data accumulates. Currently, screening for biological receptor activity precedes or is concurrent with screening for properties related to``drugability.'' In the future,`d rugability'' screening may precede biological receptor activity screening. The level of permeability or solubility needed for oral absorption is related to potency. The relative importance of poor solubility and poor permeability towards the problem of poor oral absorption depends on the research approach used for lead generation. A``rational drug design'' approach as exemplified by Merck advanced clinical candidates leads to time-dependent higher molecular weight, higher H-bonding properties, unchanged lipophilicity, and, hence, poorer permeability. A high throughput screening (HTS)-based approach as exemplified by unpublished data on Pfizer (Groton, CT) early candidates leads to higher molecular weight, unchanged H-bonding properties, higher lipophilicity, and, hence, poorer aqueous solubility. D

An In silico study was carried out on a series of novel quinoline based inhibitors which were designed, synthesized and assessed for their in vitro activity versus the human colon cancer cell line HT29 and the human breast cancer cell line MDA-MB231 by Arafa RK et. al. We have designed these 22 inhibitors in ChemBioOffice 2010 and minimized using the LigPrep tool of Schrödinger 2011. Docking study of these inhibitors was performed on different cancer proteins in order to give a suggestion to the proposed in vitro mechanism of action. Some prominent cancer proteins specifically causing breast and colon cancers are used as targets in this computational study to predict the most active quinoline based derivative. The proteins are minimized using the protein preparation wizard and Grid is generated by specifying the active site amino acids. The binding model of best scoring inhibitor with each protein was assessed from their G-scores and disclosed by docking analysis using the XP visualizer tool. Interestingly the result of docking was found to match with the previous invitro study where the most active derivative against both tested cell lines was the Schiff's base 4e. The pharmacokinetic parameters study was done using the QikProp 3.4 tool to display ADME and toxicity properties of these inhibitors.

- by Manoj Kumar
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- Cancer, Docking, Quinoline, ADME

This review starts with an introduction on the theoretical aspects of biopharmaceutics and developments in this field from mid-1950s to late 1970s. It critically addresses issues related to fundamental processes in oral drug absorption such as the complex interplay between drugs and the gastrointestinal system. Special emphasis is placed on drug dissolution and permeability phenomena as well as on the mathematical modeling of oral drug absorption. The review ends with regulatory aspects of oral drug absorption focusing on bioequivalence studies and the US Food and Drug Administration and European Medicines Agency guidelines dealing with Biopharmaceutics Classification System and Biopharmaceutic Drug Disposition Classification System.

- by Vangelis D . Karalis and +1
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- Europe, Permeability, Pharmaceutical Sciences, United States

and sharing with colleagues.

- by Neil Parrott
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- Drug Discovery, Prodrug, Intestinal absorption, Caco-2 cells

We report here new chemical series acting as antagonists of melanin-concentrating hormone receptor 1 (MCHR-1). Synthesis and structure-activity relationships are described leading to the identification of compounds with optimized in vitro pharmacological and in vitro ADME profiles. In vivo activity has been demonstrated in animal models of food intake and depression.

- by Frederic Revah
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- Organic Chemistry, Depression, Kinetics, Prediction

The formulation of protein drugs is a difficult and time-consuming process, mainly due to the complexity of protein structure and the very specific physical and chemical properties involved. Understanding protein degradation pathways is essential for the success of a biopharmaceutical drug. The present review concerns the application of high throughput screening techniques in protein formulation development. A protein high throughput formulation (HTF) platform is based on the use of microplates. Basically, the HTF platform consists of two parts: (i) sample preparation and (ii) sample analysis. Sample preparation involves automated systems for dispensing the drug and the formulation ingredients in both liquid and powder form. The sample analysis involves specific methods developed for each protein to investigate physical and chemical properties of the formulations in microplates. Examples are presented of the use of protein intrinsic fluorescence for the analysis of protein aqueous properties (e.g., conformation and aggregation). Different techniques suitable for HTF analysis are discussed and some of the issues concerning implementation are presented with reference to the use of microplates.

- by Tudor Arvinte
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- Spectroscopy, Mass Spectrometry, Fluorescence, Pharmaceutical Chemistry

Structure-activity relationships of three related series of 4-phenylthiazol-5-ylacetic acids, derived from two hits emanating from a focused library obtained by in silico screening, have been explored as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. Several compounds with double digit nanomolar binding affinity and full antagonistic efficacy for human CRTH2 receptor were obtained in all subclasses. The most potent compound was [2-(4-chloro-benzyl)-4-(4phenoxy-phenyl)-thiazol-5-yl]acetic acid having an binding affinity of 3.7 nM and functional antagonistic effect of 66 nM in a BRET and 12 nM in a cAMP assay with no functional activity for the other PGD2 DP receptor (27 lM in cAMP).

- by Marie Grimstrup
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- Organic Chemistry, Modeling, Prediction, Pharmacokinetics

Introduction: Quantitative whole-body autoradiography (QWBA) is a technique used to determine the tissue distribution of radiolabeled compounds in laboratory animals. This relatively new technique is quickly replacing wet-tissue dissection techniques, which, up to now, have been used by the pharmaceutical industry when performing tissue distribution studies to develop new drugs and to address regulatory compliance needs. In an effort to harmonize QWBA procedures across the pharmaceutical industry, the Society for Whole Body Autoradiography (SWBA) surveyed its membership to gain insight into the procedures and practices being used to perform tissue distribution studies conducted in support of drug development. Methods: The survey polled 29 respondents, who represent pharmaceutical companies in the United States, Europe, and Asia. Participants answered approximately 50 questions related to study design, applications, autoradiography methods, tissue quantitation, and regulatory compliance. Results: The survey revealed general consistencies and inconsistencies among the labs that responded. Consistencies were related to: isotope use and doses of radioactivity, number of animals per time point, exsanguination of animals, freezing methods, section thickness, tissue collection lists, section lyophilization, imaging technology, blood and calibration standards, tissues and sections sampled for quantitation, use of QWBA data for human dosimetry, and QWBA method validation. Inconsistencies were related to: number of time points used, euthanasia methods, carcass freezing time, microtome calibration, section thickness verification, sample collection, validation of commercial standards, use of background measurements during calibration, definition of limits of quantitation, reporting of extrapolated values, reexposure of section to determine low levels, computer system validation, definitions of raw data, audit trail documentation, studies performed under Good Laboratory Practices (GLP) vs. non-GLP conditions. Discussion: The survey indicated that most labs are now using QWBA to perform their tissue distribution studies and that these data have been submitted and accepted by regulatory authorities around the world. Procedures and practices involved in the design of these studies appear to vary somewhat. An important inconsistency found related to the number of time points used to determine the pharmacokinetic (PK) parameters for tissues, which may effect the reliability of these parameters for use in predicting human exposure to radioactivity during human radiolabeled studies. Survey results regarding QWBA methods indicated that there is a lot of consistency across surveyed labs; however, there are some inconsistent areas that raise regulatory compliance issues and these are related to the verification of section thickness, validation of commercial standards and their use in quantitation, definitions of limits of quantitation, and consideration of background measurements during quantitation. This survey provides autoradiographers, managers, and regulators with an important reference on the state-of-the art of QWBA and shows that the technique has gained wide acceptance across the pharmaceutical industry. However, it also shows that there are some key areas, such as inconsistencies in the procedures used for quantitation, that investigators may want to probe further to assure that the highest quality and most useful studies are performed. D

- by eric solon
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- Drug development, Pharmaceutical industry, Data Collection, Autoradiography

Quantitative predictions of pharmacokinetics (PKs) and concentration-time profiles using in vitro and in vivo preclinical data are critical to estimate systemic exposures for first-in-human studies. Prospective prediction accuracies of human PKs for 18 compounds across all Biopharmaceutics Classification System/Biopharmaceutics Drug Disposition Classification System classes were evaluated. The a priori predicted profiles were then compared with clinical profiles. Predictions were conducted using advanced compartmental absorption and transit (ACAT) physiology based PK models. Human intravenous profiles were predicted with in vivo preclinical intravenous data using Wajima formulas. Human oral profiles were generated by combining intravenous PKs together with either physiologically based oral ACAT models utilizing solubility and permeability data or by using the average bioavailability (F) and absorption rate constant (ka ) from preclinical species. Key PK parameters evaluated were the...

- by Tycho Heimbach
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- Algorithms, Pharmacokinetics, Pharmaceutical Chemistry, Computer Simulation

Activation of the newly identified σ 1 chaperone protein is involved in several aspects of the psychostimulant and addictive effects of cocaine. The development of ligands that selectively target the σ 1 protein may lead to putative potent anti-cocaine agents. Here, we synthetized substituted hydantoins with high affinity for the σ 1 protein and evaluated their behavioral efficacy. Two pure enantiomers were designed and synthesized: tetrahydroisoquinoleine-hydantoin fused compounds 3 and 4. They increased cocaine-induced locomotor stimulation or sensitization. The most active enantiomer 4, facilitated CPP acquisition but failed to substitute for cocaine. When CPP was acquired with cocaine and then extinguished, 4 provoked reactivation of CPP. These observations showed that compound 4 shows a typical profile of σ 1 protein activator, facilitating cocaine-induced behavioral effects. Preliminary ADME properties are in favour of an optimal therapeutic development. Such Tichydantoin compound may serve as a new effective agonist therapy in cocaine addiction.

- by Catherine Foulon
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- Animal Behavior, Locomotion, Enzyme Inhibitors, HPLC

The application of a fully integrated and automated virtual screening method for identifying potential and novel inhibitors of bovine lmwPTP is described. The protocol makes extensive use of our recently introduced LINGO tools, which allow the extraction of the implicit chemical information present in SMILES representations. Nine out of 34 compounds selected from a database of almost 500 000 commercially available compounds were experimentally confirmed to be competitive inhibitors of lmwPTP, two of them showing K i values around 10 mM. The best inhibitors previously described had K i values higher than 1 mM. These results constitute an experimental validation of our virtual screening algorithm and provide a basis for the optimization of pharmacologically interesting lmwPTP inhibitors.

- by Federico Melo
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- Algorithms, Organic Chemistry, Modeling, Enzyme Inhibitors

In the present study, time-dependent variations of drug-metabolising enzyme activities (DMEs) in primary cultures of rabbit hepatocytes, a species of economic importance in Mediterranean countries, were investigated. Cross-bred rabbits were anesthetised and their livers perfused in situ by a two-step collagenase technique; cells suspensions were filtered, seeded in collagen-coated dishes and cultivated at 37 C in a controlled atmopshere for 24 and 72 h. Cytochrome P450 and b 5 contents as well as the catalytic activity of some P450dependent monooxygenases were measured in subcellular fractions obtained by differential ultracentrifugation; microsomal proteins were also subjected to immunoblotting, using antibodies to rat P4501A, 2B, 2E1 and 3A isoforms. The activity of some microsomal hydrolytic enzymes was also determined. As regards conjugative enzymes, glutathione content and activities of glutathione S-transferase, uridindiphosphoglucuronosyl-transferase, acetyl-transferase and 1,2-epoxibuthane glutathione transferase were assayed. An overall reduction of the catalytic activity was observed 72 h after plating, reaching in certain instances the level of statistical significance. On the whole, our data confirm those previously reported with hepatocytes obtained from other species; however, the evidence that DMEs were still measurable after 72 h supports the usefulness of this in vitro method for drug metabolism studies in the rabbit as well. #

- by Carlo Nebbia
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- Kinetics, Drug metabolism, Antibodies, ETA

- by tudor Arvinte
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- Spectroscopy, Mass Spectrometry, Fluorescence, Pharmaceutical Chemistry

Thirteen novel seco-DCK analogs (4-16) with several new skeletons were designed, synthesized and screened for in vitro anti-HIV-1 activity. Among them, three compounds (5, 13, and 16) showed moderate activity, and compound 9 exhibited the best activity with an EC 50 value of 0.058 μM and a therapeutic index (TI) of 1000. The activity of 9 was better than that of 4-methyl DCK (2, EC 50 : 0.126 μM, TI: 301.2) in the same assay. Additionally, 9 also showed antiviral activity against a multi-RT inhibitor-resistant strain (RTMDR), which is insensitive to most DCK analogs. Compared with 2, compound 9 has a less complex structure, fewer hydrogen-bond acceptors, and a reduced log P value. Therefore, it is likely to exhibit better ADME, and appears to be a promising new lead for further development as an anti-HIV candidate.

- by Jian Tang
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- Organic Chemistry, Cell line, In Vitro, Virus

In this work, a review of the apparatuses available to mimic what happens to a drug (or to foodstuffs) once ingested is presented. Similarly, a brief review of the models proposed to simulate the fate of a drug administered to a living body is reported. Then, the release kinetics of extended release of diclofenac from a commercial enteric-coated tablet was determined both in a conventional dissolution tester (USP Apparatus 2, Method A) as well as in an apparatus modified to reproduce a given pH evolution, closer to the real one than the one suggested by USP. The two experimental release profiles were reported and discussed; therefore, they were adopted as input functions for a previously proposed pharmacokinetic model. The obtained evolutions with time of plasma concentration were presented and used to assess the effectiveness of the commercial pharmaceutical products. The importance of a correct in vitro simulation for the design of pharmaceutical dosage systems was thus emphasized.The kinetic of the drug release, and the subsequent ADME phenomena, are strongly influenced by the dissolution conditions.

- by Gaetano Lamberti and +2
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- Kinetics, Pharmacokinetics, Pharmaceutical Chemistry, Absorption

One of the drug specific parameters needed in physiologically based pharmacokinetic (PBPK) models is the tissue to plasma drug concentration ratios (K p values). The aim of this study was to develop an empirical method for predicting K p values using a preclinically determined in vivo volume of distribution, in combination with descriptors for drug lipophilicity. Pharmacokinetic data in laboratory animals for a wide range of drug compounds were collected. Obtained correlations between K p values for muscle and other tissues, in a training set of 49 compounds, were used to predict K p values for a test set of 22 compounds, based on their volume of distribution and lipophilicity. Predicted K p values agreed well with experimentally determined values (n ¼ 118), especially for noneliminating tissues (r 2 ¼ 0.81) with 72% and 87% being within a factor AE2 and AE3, respectively. In conclusion, we present an empirical method based on a measured volume of distribution and a drug lipophilicity descriptor, which can be used to predict tissue K p values with reasonable accuracy. ß

- by Ulf Bredberg
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- Prediction, Pharmacokinetics, DISTRIBUTION, Adipose tissue

Understanding the development of a scientific approach is a valuable exercise in gauging the potential directions the process could take in the future. The relatively short history of applying computational methods to absorption, distribution, metabolism and excretion (ADME) can be split into defined periods. The first began in the 1960s and continued through the 1970s with the work of Corwin Hansch et al. Their models utilized small sets of in vivo ADME data. The second era from the 1980s through 1990s witnessed the widespread incorporation of in vitro approaches as surrogates of in vivo ADME studies. These approaches fostered the initiation and increase in interpretable computational ADME models available in the literature. The third era is the present were there are many literature data sets derived from in vitro data for absorption, drug ± drug interactions (DDI), drug transporters and efflux pumps [P-glycoprotein (P-gp), MRP], intrinsic clearance and brain penetration, which can theoretically be used to predict the situation in vivo in humans. Combinatorial synthesis, high throughput screening and computational approaches have emerged as a result of continual pressure on pharmaceutical companies to accelerate drug discovery while decreasing drug development costs. The goal has become to reduce the drop-out rate of drug candidates in the latter, most expensive stages of drug development. This is accomplished by increasing the failure rate of candidate compounds in the preclinical stages and increasing the speed of nomination of likely clinical candidates. The industry now understands the reasons for clinical failure other than efficacy are mainly related to pharmacokinetics and toxicity. The late 1990s saw significant company investment in ADME and drug safety departments to assess properties such as metabolic stability, cytochrome P-450 inhibition, absorption and genotoxicity earlier in the drug discovery paradigm. The next logical step in this process is the evaluation of higher throughput data to determine if computational (in silico) models can be constructed and validated from it. Such models would allow an exponential increase in the number of compounds screened virtually for ADME parameters. A number of researchers have started to utilize in silico, in vitro and in vivo approaches in parallel to address intestinal permeability and cytochrome P-450-mediated DDI. This review will assess how computational approaches for ADME parameters have evolved and how they are likely to progress.

- by jim wikel
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- Catalysis, Drug Discovery, Pharmacokinetics, Drug development

A capillary isoelectric focusing (cIEF) method was developed for the determination of the ionization constants (pK a ) of small molecules. Two approaches used to decrease the electroosmotic flow (EOF) were compared: (i) a hydroxypropylcellulose (HPC) coated capillary in aqueous medium and (ii) the addition of glycerol to act as a viscosifying agent. The cIEF method with the glycerol medium was selected, and the ionization constants of 22 basic and 21 acidic compounds, including 15 pharmaceutical drugs, were determined, resulting in pK a values from 3.5 to 7.4 and 6.4 to 9.3, respectively. cIEF offers an interesting alternative to other techniques for pK a determination with low sample consumption, high throughput and low cost.

- by Jean-luc Veuthey
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- Cellulose, Pi, Glycerol, Molecular weight

Extensive SAR studies and optimization of ADME properties of benzimidazol-2-one derivatives led to the identification of BMS-433771 (3) as an orally active RSV fusion inhibitor. In order to extend the structure-activity relationships for this compound series, substitution of the benzimidazole ring was examined with a view to establishing additional productive interactions between the inhibitor and functionality present in the proposed binding pocket. Amongst the compounds synthesized, the 5-aminomethyl analogue 10aa demonstrated potent antiviral activity towards wild-type RSV and retained excellent inhibitory activity towards a virus that had been developed to express resistance to BMS-433771 (3), data consistent with an additional productive interaction between the inhibitor and the fusion protein target.

- by Ivette Medina
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- Organic Chemistry, Physical Chemistry, Water, Modeling

A range of heterocycle fused azepines were synthesized in order to find a CNS penetrant, selective 5-HT 2C agonist for the treatment of incontinence. The pyridazo-azepines such as compound 11 were shown to be potent 5-HT 2C agonists and have potential for CNS penetration and good in vitro ADME properties but lacked selectivity against 5-HT 2B . Fusing a further heterocycle gave the selective triazolopyrimido-azepines. An example of this series, compound 36, was shown to be potent, selective, metabolically stable in vitro and efficacious in an in vivo model of stress urinary incontinence.

- by Kelly Conlon
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- Organic Chemistry, Treatment, Drug Discovery, Pharmacokinetics

Quantitative Structure-Property Relationship models (QSPR) based on in vivo blood-brain permeation data (logBB) of 88 diverse compounds, 324 descriptors and a systematic variable selection method, namely ÔVariable Selection and Modeling method based on the prediction (VSMP)Õ, are reported. Of all the models developed using VSMP, the best three-descriptors model is based on Atomic type E-state index (SsssN), AlogP98 and Van der WaalÕs surface area (r = 0.8425, q = 0.8239, F = 68.49 and SE = 0.4165); the best four-descriptors model is based on Kappa shape index of order 1, Atomic type E-state index (SsssN), Atomic level based AI topological descriptor (AIssssC) and AlogP98 (r = 0.8638, q = 0.8472, F = 60.982 and SE = 0.3919). The performance of the models on three test sets taken from the literature is illustrated and compared with the results from other reported computational approaches. Test set III constitutes 91 compounds from the literature with known qualitative BBB indication and is used for virtual screening studies. The success rate of the reported models is 82% in the case of BBB+ compounds and a similar success rate is observed with BBBÀ compounds. Finally, as the models reported herein are based on computed properties, they appear as a valuable tool in virtual screening, where selection and prioritization of candidates is required.

- by Sitarama Gunturi
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- Organic Chemistry, Computational Biology, Modeling, Prediction

A novel elemanolide with an a-methyl-c-lactone moiety, 8a-O-(4-hydroxy-2-methylenebutanoyloxy)melitensine, in addition to four known sesquiterpene lactones also bearing the same lactone ring, melitensin, 11b,13 dihydrosalonitenolide, 8a-hydroxy-11b,13-dihydro-4-epi-sonchucarpolide, and 8a-hydroxy-11b,13-dihydro-onopordaldehyde have been isolated from the aerial parts of Centaurea pullata. The in vitro antibacterial and antifungal activities of the isolated sesquiterpene lactones were tested against six bacteria and eight fungal species, using a microdilution method. All compounds tested showed greater antibacterial and antifungal activities than the positive controls used. Moreover, the pharmacokinetic profile of these compounds was investigated using computational methods.

- by Catherine Koukoulitsa
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- Organic Chemistry, Prediction, Pharmacokinetics, Pharmacognosy
- by Elisabetta Chiarparin
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- Biomimetics, Drug Discovery, Pharmacokinetics, Pharmaceutical Sciences

Pyrazole derivatives R 0180 3-Amino-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: A New Class of CDK2 Inhibitors. -The solution-phase synthesis and early expansion of title pyrrolopyrazoles toward CDK2/cyclin A inhibitors is described.... more

- by Paolo Pevarello
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- Organic Chemistry, Enzyme Inhibitors, Macromolecular X-Ray Crystallography, FACS

Here, we describe the selection and optimization of a chemical series active in both a full-length and a fragmentbased Huntington's disease (HD) assay. Twenty-four thousand small molecules were screened in a phenotypic HD assay, identifying a series of compounds bearing a 3-hydroxy-3trifluoromethylpyrazole moiety as able to revert the toxicity induced by full-length mutant Htt by up to 50%. A chemical exploration around the series led to the identification of compound 4f, which demonstrated to be active in a Htt171− 82Q rat primary striatal neuron assay and a PC12-Exon-1 based assay. This compound was selected for testing in R6/2 mice, in which it was well-tolerated and showed a positive effect on body weight and a positive trend in preventing ventricular volume enlargment. These studies provide strong rationale for further testing the potential benefits of 3-hydroxy-3trifluoromethylpyrazoles in treating HD.

- by ozgun gokce
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- Organic Chemistry, ADME
- by Stribor Marković
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- Organic Chemistry, Medicinal Chemistry, Catalysis, Modeling

S 5 4 1 3 5 9 -6 4 4 6 1 0 1 4 -see front matter

- by Adm San
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- Drug Discovery, Prediction Model, IDEA, ADME

This study determined the oral and dermal ADME of 2-amino-2-methyl-1-propanol (AMP), a substituted aliphatic alcohol used in a number of industrial and consumer products. Groups of 4 male Fischer 344 rats received either a single bolus oral or dermal dose of 18 mg/kg (14)C-AMP in water. The dermal dose was applied to an area of 12 cm(2) on the back of the rats for 6h under semi-occluded conditions and fitted with rodent jackets to prevent grooming. Time-course blood and excreta were collected, radioactivity determined and blood and urine analyzed for AMP and metabolites. The orally administered (14)C-AMP was rapidly absorbed and eliminated in urine. Elimination of radioactivity from blood was biphasic with a rapid alpha phase (t(1/2 alpha) approximately 1h) followed by a slower beta phase (t(1/2 beta)=41+/-4h plasma and 69+/-34 h RBC). Total urinary elimination accounted for 87-93% of the dose, most (72-77%) within the first 48 h. Fecal elimination accounted for only 3-10%. Only 3-4% of the dose was found in tissues 168h post-dosing. The total dermal absorption of (14)C-AMP was 42% that included approximately 8% of the dose remaining at the application site 162 h after washing. Less than 1% of the applied dose remained in the stratum corneum and approximately 6% of the dose was found in tissues. Urinary elimination was 43% of the administered dose, most ( approximately 17%) within 48 h, and approximately 2% was eliminated in feces. It took much longer to reach plasma C(max) after dermal application (8.5+/-4.7 h in plasma and 4.0+/-2.8h in RBC) than the oral dose (0.3h) and the AUC(0--&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;alpha) for dermal dose was approximately 8-fold lower than with the oral dose. Again, elimination of the radioactivity from blood was biphasic with apparent t(1/2 alpha) of 9+/-6 and 2+/-1h for plasma and RBC, respectively. However, the alpha phase was &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;flipped-flopped&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; due to relatively slow dermal penetration and rapid elimination of the systemically absorbed dose, which was corrected to approximately 0.3 h after separating alpha elimination phase from the absorption. The slope of the beta phase became parallel to the oral route upon cessation of the absorption from the dose site skin, between 18 and 42 h post-washing. No metabolite of AMP was detected either in blood or excreta of any rat. Results of this study suggests that toxicologically significant concentrations of AMP are unlikely to be achieved in the systemic circulation and/or target tissues in humans as a result of dermal application of products containing AMP. Additionally, systemically absorbed dose will be rapidly eliminated from the body with little remaining at the application site.

- by Shakil Saghir
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- Chemistry, Design, Kinetics, Mass Spectrometry

A series of hydroxy and phenolic compounds have been assayed for the inhibition of two physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic human isozymes I and II. The investigated molecules showed inhibition constants in the range of 1.07-4003 and 0.09-31.5 mM at the hCA I and hCA II enzymes, respectively. In order to investigate the binding mechanisms of these inhibitors, in silico studies were also applied. Molecular docking scores of the studied compounds are compared using three different scoring algorithms, namely Glide/SP, Glide/XP and Glide/IFD. In addition, different ADME (absorption, distribution, metabolism and excretion) analysis was performed. All the examined compounds were found within the acceptable range of pharmacokinetic profiles.

- by Ramin Ekhteiari Salmas
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- Algorithms, Kinetics, Computer Simulation, Phenols

Syntheses and biological activities of imidazo-, pyrimido-and diazepino[2,1-f]purinediones containing N-alkyl substituents (with straight, branched or unsaturated chains) are described. Tricyclic derivatives were synthesized by the cyclization of 8-bromo-substituted 7-(2-bromoethyl)-, 7-(3chloropropyl)-or 7-(4-bromobutyl)-theophylline with primary amines under various conditions. Compound 22 with an ethenyl substituent was synthesized by dehydrohalogenation of 9-(2-bromoethyl)-1,3-dimethyltetrahydropyrimido[2,1-f] purinedione. The obtained derivatives (5-35) were initially evaluated for their affinity at rat A 1 and A 2A adenosine receptors (AR), showing moderate affinity for both adenosine receptor subtypes. The best ligands were diazepinopurinedione 28 (K i =0.28 μM) with fivefold A 2A selectivity and the nonselective A 1 /A 2A AR ligand pyrimidopurinedione 35 (K i A 1 = 0.28 μM and K i A 2A =0.30 μM). The compounds were also evaluated for their affinity at human A 1 , A 2A , A 2B and A 3 ARs. All of the obtained compounds were docked to the A 2A AR Xray structure in complex with the xanthine-based, potent adenosine receptor antagonist-XAC. The likely interactions of imidazo-, pyrimido-and diazepino[2,1-f]purinediones with the residues forming the A 2A binding pocket were discussed. Furthermore, the new compounds were tested in vivo as anticonvulsants in maximal electroshock, subcutaneous pentylenetetrazole (ScMet) and TOX tests in mice (i.p.). Pyrimidopurinediones showed anticonvulsant activity mainly in the ScMet test. The best derivative was compound 11, showing 100 % protection at a dose of 100 mg/kg without symptoms of neurotoxicity. Compounds 6, 7, 8 and 14 with short substituents showed neurotoxicity and caused death. In rat tests (p.o.), 9 was characterized by a high protection index (>13.3). AR affinity did not apparently correlate with the antiepileptic potency of the compounds.

- by Vikas Yadav
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- Organic Chemistry, Medicinal Chemistry, Modeling, Prediction

Introduction: Radioluminography, or phosphor imaging, is often used in rodent quantitative whole-body autoradiography (QWBA) studies to determine the tissue distribution and pharmacokinetic (PK) parameters of new pharmaceutical entities in rodents. The rodent tissue pharmacokinetics information are then used to predict human radiation exposure to 14 C or 3 H during human radioisotope mass balance studies. The human dosimetry estimation can be biased by the method used to determine the lower limit of quantitation (LOQ) of the phosphor imager. A survey of autoradiographers revealed that at least five different methods are used to determine phosphor imager LOQ. The objective of this study is to compare and evaluate the human dosimetry estimates obtained by applying those five LOQ methods to a single set of WBA data. Methods: Five different phosphor imager LOQ determination methods were applied to a single set of QWBA rodent tissue distribution data to produce five tissue concentration time profiles. Tissue PK parameters were determined for each profile and subsequently used to calculate the 14 C exposure for a proposed human 14 C mass balance study. Results: A threefold difference was observed among the five predictions of human 14 C exposure when the five different phosphor imager LOQ values were applied to the initial data set. Discussion: The method chosen to determine the phosphor imaging LOQ for QWBA rodent tissue distribution study could impact the human 14 C exposure estimates. The end result may either under-or overestimate the 14 C-tissue exposure in humans during radioisotope studies, depending on the method used to determine LOQ. We recommend two approaches to reduce the variations in the determination of rodent tissue distribution pharmacokinetics: (1) Set more sampling time points to cover the terminal phase to obtain more accurate t 1/2 and (2) use Method 3 or the small sized sampling tool of Method 5 for LOQ determinations because it is a balanced approach for both simplicity and accuracy. D

- by eric solon
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- Forecasting, Pharmacokinetics, Radiometry, Radiation Exposure

Novel 2-imidazoles have been identified as potent partial agonists of the a 1A adrenergic receptor, with good selectivity over the a 1B , a 1D and a 2A receptor sub-types. Sulfonamide 23 possessed attractive drug-like properties with... more

- by Kelly Conlon
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- Organic Chemistry, Pharmacokinetics, Urinary incontinence, In Vitro
- by Vikas Yadav
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- Organic Chemistry, Medicinal Chemistry, Catalysis, Modeling

Novel 2-(Substituted)-3-{[substituted]amino}quinazolin-4(3H)-one. -Synthesis and anticonvulsant activity of title compounds (III) and (V) are reported. The most active derivative in the series of thirty novel compounds is found to be (Ve). A computational study is carried out as well for calculation of pharmacophore pattern and prediction of pharmacokinetic properties. -(KUMAR*, P.; SHRIVASTAVA, B.; PANDEYA, S. N.; STABLES, J. P.; Eur.

- by Praveen Kumar
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- Genetics, Algorithms, Organic Chemistry, Modeling

The family of phosphodiesterases (PDE's) regulate levels of secondary messengers adenosine and guanosine 3′,5′-cyclic monophosphates (cAMP and cGMP, respectively) via hydrolysis to their corresponding inactive 5′-monophosphate... more

- by Natalie Pham
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- Chemistry, Organic Chemistry, Medicine, Cell line
- by ghada ahmed
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- Drug Discovery, Pharmacokinetics, Computer Simulation, Pharmaceutical Sciences
- by Susan Euling
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- Genomics, RNA, Systems Biology, Risk assessment

Polyspecific proteins, such as the cytochrome P450 enzyme family, the hERG potassium channel and the ABC-type multidrug efflux pumps ABCB1, ABCC1 and ABCG2 are increasingly recognised as playing a major role in bioavailability and toxicity of drugs. Although considerable efforts have been undertaken to establish in silico tools for predicting drug–protein interactions, especially in the field of ABC pumps, general applicable models are still rare. We recently showed that similarity-based descriptors are a versatile tool for prediction of ABCB1 (P-glycoprotein, P-gp) inhibitory activity. These descriptors are based on the calculation of similarity values between the compounds of the training set to a group of reference set compounds. The similarity values are subsequently used as independent variables in QSAR analyses. Within this paper, we address the influence of the reference set on the predictive ability of QSAR models for a set of 412 inhibitors of the multidrug efflux pump ABCB1. Four different reference sets were designed comprising highly diverse, drug-like compounds (A), a subset of the training set compounds (B), a set of manually selected ABCB1 inhibitors (C) and low molecular weight chemicals (D). Our results indicate that a combination of high diversity and an interaction of the reference compounds with the biological target is beneficial for yielding good models. The reference dataset tailored to the specific problem (the biological target) scored best in predicting the biological activity of compounds from an external test set.

The disposition of three 4-aminoquinoline leads, namely isoquine (ISO), des-ethyl isoquine (DEI) and N-tert-butyl isoquine (NTBI), were studied in a range of in vivo and in vitro assays to assist in selecting an appropriate candidate for further development. Analogous to amodiaquine (ADQ), ISO undergoes oxidative N-dealkylation to form DEI in vivo. Blood clearance of DEI was as much as 10-fold lower than that of ISO in animals and after oral administration, metabolite exposure exceeded that of parent by as much as 14-fold. Replacement of the N-ethyl with an N-tert-butyl substituent substantially reduced N-dealkylation as blood clearance of NTBI was ∼2 to 3-fold lower than DEI in mouse, rat, dog and monkey. Mean NTBI oral bioavailability was generally higher than the other leads (≥68%). Blood cell association was substantial for NTBI, particularly in dog and monkey, where blood to plasma concentration ratios >4 were observed. Human plasma protein binding was similar for NTBI, DEI, and des-ethyl amodiaquine (DEA). Allometric scaling predicted human blood clearance (CL) for NTBI to be low (∼12% liver blood flow). All the 4-aminoquinolines inhibited recombinant human cytochrome P450 2D6 with similar potency; DEI also inhibited 1A2. On balance, NTBI appeared the most promising lead to progress towards full development. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:362–377, 2009

- by Ganesh Moorthy
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- Drug metabolism, Dogs, Mice, Pharmaceutical Sciences

- by Trond Ulven
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- Organic Chemistry, Modeling, Prediction, Pharmacokinetics

- by daniel silva
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- Organic Chemistry, Medicinal Chemistry, Molecular modeling, Acetylcholinesterase

It has been reported that values of tissue-plasma ratios (K p ) and resulting volume of distribution at steady state (V ss ) are substantially overpredicted for several highly lipophilic drugs. This effect was observed particularly with the published version of the tissuecomposition-based model, which used experimentally determined unbound fraction in plasma (fu p ) as input for drugs. The reasons for the unreasonably high V ss predictions were investigated in this study for 14 highly lipophilic compounds with a log n-octanol-water partition coefficient (log P ow ) of at least 5.8. Here, we argue that the experimentally determined fu p is inaccurate for these compounds, which affected the prediction of K p and V ss . Alternatively, the tissueplasma ratio of neutral lipids (nl) equivalent was used as the main factor governing K p , and hence V ss , in addition to log P ow . The average fold error of deviation between the predicted and observed human V ss is 124 for the published model, whereas it significantly decreased to 1.5 for the proposed model. The sensitivity analysis confirmed the importance of nl content and drug lipophilicity. Overall, this study proposes a generic and simplified tissue-composition-based model for highly lipophilic drugs and chemicals, which is a step forward toward improving prediction of V ss into physiologically based pharmacokinetic (PBPK) models.

- by Sami Haddad
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- Pharmacokinetics, DISTRIBUTION, Pharmaceutical Sciences, Disposition

The analytical methods for the determination of phytoestrogenic compounds in edible plants, plant products and biological matrices are reviewed. The detection, qualitative and quantitative methods based on different chromatographic separations of gas chromatography (GC), high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE) coupled with various detections by ultraviolet absorption (UV), electrochemical detection (ED), fluorescence detection, mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR), as well as non-chromatographic immunoassay are each extensively examined and compared. An overview on phytoestrogen chemistry, bioactivities and health effects, plant precursors, metabolism and sample preparation is also presented.

- by Jim Simon
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- Chemistry, Analytical Chemistry, Drug Discovery, Capillary electrophoresis

A series of new deoxyamodiaquine-based compounds was synthesized via the modified TMSN3-Ugi multi-component reaction and evaluated in vitro for antiplasmodial activity. The most potent compounds, 6b, 6c and 6j, showed IC50 values in the range of 6-77nM against chloroquine-resistant K1- and W2-strains of Plasmodium falciparum. In vitro ADME characterization of frontrunner compounds 6b and 6c indicates that these two compounds are rapidly metabolized and have a high clearance rate in human and rat liver microsomes. This result correlated well with an in vivo pharmacokinetics study, which showed low bioavailability of 6c in rats. Tentative metabolite identification was determined by LC-MS and suggested metabolic lability of groups attached to the tertiary nitrogen. Preliminary studies on 6b and 6c suggested strong inhibitory activity against the major CYP450 enzymes. In silico docking studies were used to rationalize strong inhibition of CYP3A4 by 6c. Full characterization and biological evaluation of the metabolites is currently underway in our laboratories.

- by Grace Mugumbate
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- Chemistry, Organic Chemistry, Pharmacokinetics, HPLC