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

Kulén M, Núñez-Otero C, Cairns AG, Silver J, Lindgren AEG, Wede E, Singh P, Vielfort K, Bahnan W, Good JAD, Svensson R, Bergström S, Gylfe Å, Almqvist F

Med. Chem. Commun. 10 (11) 1966-1987 [2019-11-01; online 2019-10-17]

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.

Drug Discovery and Development (DDD) [Service]

PubMed 32206238

DOI 10.1039/c9md00405j

Crossref 10.1039/c9md00405j

pii: c9md00405j
pmc: PMC7069368

Publications 9.5.0