1. Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based Chlamydia trachomatis inhibitors
- Author
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Kulén, Martina, Núñez-Otero, Carlos, Cairns, Andrew G., Silver, Jim, Lindgren, Anders E. G., Andersson, Emma K., Singh, Pardeep, Vielfort, Katarina, Bahnan, Wael, Good, James A. D., Svensson, Richard, Bergström, Sven, Gylfe, Åsa, Almqvist, Fredrik, Kulén, Martina, Núñez-Otero, Carlos, Cairns, Andrew G., Silver, Jim, Lindgren, Anders E. G., Andersson, Emma K., Singh, Pardeep, Vielfort, Katarina, Bahnan, Wael, Good, James A. D., Svensson, Richard, Bergström, Sven, Gylfe, Åsa, and Almqvist, Fredrik
- 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.
- Published
- 2019
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