Key result
3,5-dialkoxypyridine analogues of bedaquiline demonstrated potent in vitro and in vivo anti-tubercular activity with greatly attenuated hERG blockade.
Why the study?
Bedaquiline is clinically effective against drug-resistant tuberculosis but causes QT prolongation via potent hERG channel inhibition, prompting the search for potent diarylquinolines with lower lipophilicity, higher clearance, and lower risk for QT prolongation.
Novel bedaquiline analogues with a 3,5-dialkoxy-4-pyridyl substitution show potent anti-tuberculosis activity while minimizing hERG channel inhibition, potentially reducing the risk of QT prolongation.
These analogues may reduce QT risk in TB therapy; leaves open human translation and clinical testing.
Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.
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Sutherland et al. (2019) studied Tuberculosis. 3,5-dialkoxypyridine analogues of bedaquiline vs. Bedaquiline was evaluated on Anti-tubercular activity and hERG blockade. 3,5-dialkoxypyridine analogues of bedaquiline demonstrated potent in vitro and in vivo anti-tubercular activity with greatly attenuated hERG blockade.
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