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      Application of biomimetic HPLC to estimate in vivo behavior of early drug discovery compounds

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          Abstract

          Characterizing the properties of large numbers of compounds and estimating their potential absorption, distribution, metabolism and elimination properties are important early stages in the process of drug discovery and help to reduce later stage attrition. The chromatographic separation principles using stationary phases that contain proteins and phospholipids are more suitable for compound characterization and estimation of the pharmacokinetic properties than the traditional octanol/water partition coefficient. This technology, when standardized, enables the prediction of in vivo behavior and the selection of compounds with the best potential, thus reducing the number of animal experiments. Chromatography may be involved more widely in the future to measure kinetic aspects of compounds’ binding to proteins and receptors which would enable designing compounds that require a lower frequency of doses and have more predictable pharmacokinetic profiles.

          Lay abstract

          The measurement of the molecular properties of potential drug molecules is now an established component of modern drug design strategies. Chromatographic separation now plays an essential role in this process in the estimation of pharmacokinetic properties and may be extended in the future to protein and receptor binding kinetics. These strategies will also offer cost savings and reduce the need for animal experiments.

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          Most cited references 54

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          Scales of solute hydrogen-bonding: their construction and application to physicochemical and biochemical processes

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            Physiochemical drug properties associated with in vivo toxicological outcomes.

            Relationships between physicochemical drug properties and toxicity were inferred from a data set consisting of animal in vivo toleration (IVT) studies on 245 preclinical Pfizer compounds; an increased likelihood of toxic events was found for less polar, more lipophilic compounds. This trend held across a wide range of types of toxicity and across a broad swath of chemical space.
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              The impact of aromatic ring count on compound developability--are too many aromatic rings a liability in drug design?

              The impact of aromatic ring count (the number of aromatic and heteroaromatic rings) in molecules has been analyzed against various developability parameters - aqueous solubility, lipophilicity, serum albumin binding, CyP450 inhibition and hERG inhibition. On the basis of this analysis, it was concluded that the fewer aromatic rings contained in an oral drug candidate, the more developable that candidate is probably to be; in addition, more than three aromatic rings in a molecule correlates with poorer compound developability and, thus, an increased risk of attrition in development. Data are also presented that demonstrate that even within a defined lipophilicity range, increased aromatic ring count leads to decreased aqueous solubility.
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                Author and article information

                Journal
                FDD
                Future Drug Discovery
                Future Drug. Discov.
                Future Drug Discovery
                Newlands Press Ltd (London, UK )
                2631-3316
                July 2019
                26 April 2019
                : 1
                : 1
                Affiliations
                1Bio-Mimetic Chromatography Ltd, Unit 5B Business & Technology Centre, Bessemer Drive, Stevenage, SG1 2DX, UK
                2UCL School of Pharmacy, 29–39 Brunswick Square, London, WC1N 1AX, UK
                Author notes
                *Author for correspondence: k.valko@ 123456ucl.ac.uk
                10.4155/fdd-2019-0004
                © 2019 Klara L Valko

                This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License

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