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Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based Chlamydia trachomatis inhibitors.
Kulén, Martina; Núñez-Otero, Carlos; Cairns, Andrew G; Silver, Jim; Lindgren, Anders E G; Wede, Emma; Singh, Pardeep; Vielfort, Katarina; Bahnan, Wael; Good, James A D; Svensson, Richard; Bergström, Sven; Gylfe, Åsa; Almqvist, Fredrik.
Afiliación
  • Kulén M; Department of Chemistry , Umeå University , 901 87 Umeå , Sweden . Email: fredrik.almqvist@umu.se.
  • Núñez-Otero C; Umeå Centre for Microbial Research , Umeå University , 901 87 Umeå , Sweden . Email: sven.bergstrom@umu.se ; Email: asa.gylfe@umu.se.
  • Cairns AG; Umeå Centre for Microbial Research , Umeå University , 901 87 Umeå , Sweden . Email: sven.bergstrom@umu.se ; Email: asa.gylfe@umu.se.
  • Silver J; Laboratory for Molecular Infection Medicine Sweden (MIMS) , Umeå University , 901 87 Umeå , Sweden.
  • Lindgren AEG; Department of Clinical microbiology , Umeå University , 901 85 Umeå , Sweden.
  • Wede E; Department of Chemistry , Umeå University , 901 87 Umeå , Sweden . Email: fredrik.almqvist@umu.se.
  • Singh P; Umeå Centre for Microbial Research , Umeå University , 901 87 Umeå , Sweden . Email: sven.bergstrom@umu.se ; Email: asa.gylfe@umu.se.
  • Vielfort K; Umeå Centre for Microbial Research , Umeå University , 901 87 Umeå , Sweden . Email: sven.bergstrom@umu.se ; Email: asa.gylfe@umu.se.
  • Bahnan W; Department of Molecular Biology , Umeå University , 901 87 Umeå , Sweden.
  • Good JAD; Laboratory for Molecular Infection Medicine Sweden (MIMS) , Umeå University , 901 87 Umeå , Sweden.
  • Svensson R; Department of Chemistry , Umeå University , 901 87 Umeå , Sweden . Email: fredrik.almqvist@umu.se.
  • Bergström S; Umeå Centre for Microbial Research , Umeå University , 901 87 Umeå , Sweden . Email: sven.bergstrom@umu.se ; Email: asa.gylfe@umu.se.
  • Gylfe Å; Umeå Centre for Microbial Research , Umeå University , 901 87 Umeå , Sweden . Email: sven.bergstrom@umu.se ; Email: asa.gylfe@umu.se.
  • Almqvist F; Department of Molecular Biology , Umeå University , 901 87 Umeå , Sweden.
Medchemcomm ; 10(11): 1966-1987, 2019 Nov 01.
Article en En | MEDLINE | ID: mdl-32206238
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Medchemcomm Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Medchemcomm Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido