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Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based Chlamydia trachomatis inhibitors
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.ORCID iD: 0000-0001-7680-0918
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
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2019 (English)In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 10, no 11, p. 1966-1987Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2019. Vol. 10, no 11, p. 1966-1987
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Pharmaceutical Sciences
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URN: urn:nbn:se:umu:diva-166479DOI: 10.1039/c9md00405jISI: 000498725400013OAI: oai:DiVA.org:umu-166479DiVA, id: diva2:1382129
Funder
Swedish Cancer SocietyKnut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineThe Kempe FoundationsSwedish Foundation for Strategic Research Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-01-02Bibliographically approved

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Kulén, MartinaNunez-Otero, CarlosCairns, Andrew G.Silver, JimLindgren, Anders E. G.Andersson, Emma K.Singh, PardeepVielfort, KatarinaBahnan, WaelGood, James A. D.Bergström, SvenGylfe, ÅsaAlmqvist, Fredrik
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Department of ChemistryUmeå Centre for Microbial Research (UCMR)Molecular Infection Medicine Sweden (MIMS)Department of Clinical MicrobiologyDepartment of Molecular Biology (Faculty of Medicine)
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