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Month: June 2010

Comparative Evaluation of 3D Virtual Ligand Screening Methods: Impact of the Molecular Alignment on Enrichment

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In the early stage of drug discovery programs, when the structure of a complex involving a target and a small molecule is available, structure-based virtual ligand screening methods are generally preferred. However, ligand-based strategies like shape-similarity search methods can also be applied. Shape-similarity search methods consist in exploring a pseudo-binding-site derived from the known small … Continued

Novel Analogs of Istaroxime, a Potent Inhibitor of Na(+),K(+)-ATPase: Synthesis, Structure-activity Relationship, and 3D-quantitative Structure-activity Relationship of Derivatives at Position 6 on the Androstane Scaffold

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We report the synthesis and biological properties of novel analogues of Istaroxime acting as positive inotropic compounds through the inhibition of the Na(+),K(+)-ATPase. We explored the chemical space around the position 6 of the steroidalscaffold by changing the functional groups at that position and maintaining a basic oximic chain in position 3.

What Does Clearance Mean?

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Drug clearance is an extremely important topic in the science of pharmacokinetics. Drug clearance defines how much drug should be administered, how frequently to dose a patient, and how two interacting drugs will affect a patient. The primary PK parameter clearance is very similar to its friend, volume of distribution. Clearance (CL) is a proportionality … Continued

A Series of 18F-labelled Pyridinylphenyl Amides as Subtype-selective Radioligands for the Dopamine D3 Receptor

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Synthesis, biological activity, and structure-selectivity relationship (SSR) studies of a novel series of potential dopamine D3 receptor radioligands as imaging agents for positron emission tomography (PET) are reported. Considering a structurally diverse library of D3 ligands, SSR studies were performed for a new series of fluorinated pyridinylphenyl amides using CoMFA and CoMSIA methods. The in … Continued

Understanding Volume of Distribution

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One of the most misunderstood pharmacokinetic (PK) parameters is volume of distribution. First of all it has numerous abbreviations (V, Vd, Vz, Vss, V1, Vc, V2, etc.), and to make matters worse, many people incorrectly define the parameter. But, once you understand the meaning behind volume of distribution, you will have a solid grasp on … Continued

Concentration–Effect Relationships for the Drug of Abuse—γ-hydroxybutyric Acid

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γ-Hydroxybutyric acid (GHB) is an endogenous neurotransmitter that is abused because of its sedative/hypnotic and euphoric effects. The objectives of this study were to evaluate the concentration-effect relationships of GHB in plasma, cerebrospinal fluid (CSF), brain (whole and discrete brain regions), and brain frontal cortex extracellular fluid. This information is crucial for future studies to … Continued

Selection of Alternative CYP3A4 Probe Substrates for Clinical Drug Interaction Studies Using In Vitro Data and In Vivo Simulation

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Understanding the potential for cytochrome P450-mediated drug-drug interactions (DDIs) is a critical step in the drug discovery process. DDIs of CYP3A4 are of particular importance because of the number of marketed drugs that are cleared by this enzyme. In response to studies that suggested the presence of several binding regions within the CYP3A4 active site, multiple probe substrates are … Continued

Molecular Docking and 3D-QSAR Studies on Triazolinone and Pyridazinone, Non-nucleoside Inhibitor of HIV-1 Reverse Transcriptase

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Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric inhibitors of the HIV-1 reverse transcriptase. Recently a series of Triazolinone and Pyridazinone were reported as potent inhibitors of HIV-1 wild type reverse transcriptase. In the present study, docking and 3D quantitative structure activity relationship (3D QSAR) studies involving comparative molecular field analysis (CoMFA) and comparative molecular similarity … Continued

Pharmacology and Safety of Glycerol Phenylbutyrate in Healthy Adults and Adults with Cirrhosis

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Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derived phenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is … Continued