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

• Published in: MedChemComm Vol. 10; no. 11; pp. 1966 - 1987
• Main Authors: Kulen, Martina, Nunez-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, Bergstrom, Sven, Gylfe, Asa, Almqvist, Fredrik
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 2019; Royal Society of Chemistry
• Subjects: Bacteria; Bioavailability; Biochemistry & Molecular Biology; Biopharmaceuticals; Cell permeability; Chemistry; Chemistry, Medicinal; Chlamydia; Chlamydia trachomatis; Condoms; Evaluation; Global health; In vivo methods and tests; Infectivity; Life Sciences & Biomedicine; Metabolism; Oral administration; Organic compounds; Permeability; Pharmacokinetics; Pharmacology; Pharmacology & Pharmacy; Science & Technology; Sexually transmitted diseases; Solubility; STD; Sulfonamides; DESIGN; MECHANISMS; PROTEIN
• ISSN: 2040-2503; 2040-2511; 2040-2511
• DOI: 10.1039/c9md00405j

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.