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

Martina Kulén, Carlos Núñez-Otero, Andrew G. Cairns, Jim Silver, Anders E. G. Lindgren, Emma Wede, Pardeep Singh, Katarina Vielfort, Wael Bahnan, James A. D. Good, Richard Svensson, Sven Bergström (Lead / Corresponding author), Åsa Gylfe (Lead / Corresponding author), Fredrik Almqvist (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)1966-1987
Number of pages22
JournalMedChemComm
Volume10
Issue number11
Early online date17 Oct 2019
DOIs
Publication statusPublished - 2019

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    Kulén, M., Núñez-Otero, C., Cairns, A. G., Silver, J., Lindgren, A. E. G., Wede, E., Singh, P., Vielfort, K., Bahnan, W., Good, J. A. D., Svensson, R., Bergström, S., Gylfe, Å., & Almqvist, F. (2019). Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based: Chlamydia trachomatis inhibitors. MedChemComm, 10(11), 1966-1987. https://doi.org/10.1039/c9md00405j