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Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based Chlamydia trachomatis inhibitors.
- Source :
-
MedChemComm [Medchemcomm] 2019 Oct 17; Vol. 10 (11), pp. 1966-1987. Date of Electronic Publication: 2019 Oct 17 (Print Publication: 2019). - Publication Year :
- 2019
-
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 <superscript>-1</superscript> 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.<br /> (This journal is © The Royal Society of Chemistry 2019.)
Details
- Language :
- English
- ISSN :
- 2040-2511
- Volume :
- 10
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- MedChemComm
- Publication Type :
- Academic Journal
- Accession number :
- 32206238
- Full Text :
- https://doi.org/10.1039/c9md00405j