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Issue 11, 2019
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Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based Chlamydia trachomatis inhibitors

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Abstract

Chlamydia trachomatis infections are a global health problem and new approaches to treat C. trachomatis with drugs of high specificity would be valuable. A library of substituted ring fused 2-pyridones has been synthesized and evaluated for their ability to attenuate C. trachomatis infectivity. In vivo pharmacokinetic studies were performed, with the best candidates demonstrating that a C8-methylsulfonamide substituent improved pharmacokinetic properties important for oral administration. C8-Methyl sulfonamide analogue 30 inhibited C. trachomatis infectivity in low micromolar concentrations. Further pharmacokinetic evaluation at an oral dose of 10 mg kg−1 showed an apparent bioavailability of 41%, compared to C8-cyclopropyl and -methoxy analogues which had negligible oral uptake. In vitro ADME (absorption, distribution, metabolism and excretion) testing of solubility and Caco-2 cell permeability revealed that both solubility and permeability is greatly improved with the C8-methyl sulfonamide 30, effectively moving it from BCS (Biopharmaceutical Classification System) class IV to II.

Graphical abstract: Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based Chlamydia trachomatis inhibitors

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Publication details

The article was received on 20 Aug 2019, accepted on 20 Sep 2019 and first published on 17 Oct 2019


Article type: Research Article
DOI: 10.1039/C9MD00405J
Med. Chem. Commun., 2019,10, 1966-1987
  • Open access: Creative Commons BY-NC license
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    Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based Chlamydia trachomatis inhibitors

    M. Kulén, C. Núñez-Otero, A. G. Cairns, J. Silver, A. E. G. Lindgren, E. Wede, P. Singh, K. Vielfort, W. Bahnan, J. A. D. Good, R. Svensson, S. Bergström, Å. Gylfe and F. Almqvist, Med. Chem. Commun., 2019, 10, 1966
    DOI: 10.1039/C9MD00405J

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