3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel |
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Authors: | Hamish S. Sutherland Amy S.T. Tong Peter J. Choi Adrian Blaser Daniel Conole Scott G. Franzblau Manisha U. Lotlikar Christopher B. Cooper Anna M. Upton William A. Denny Brian D. Palmer |
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Affiliation: | 1. Auckland Cancer Society Research Centre, School of Medical Sciences, New Zealand;2. Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand;3. Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA;4. Global Alliance for TB Drug Development, 40 Wall St, NY 10005, USA |
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Abstract: | 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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Keywords: | FROBLYAPPGEAGY-UHFFFAOYSA-N JJEGOJPMKLRSPJ-UHFFFAOYSA-N VCZLKKRCINFNGE-UHFFFAOYSA-N GQTLJYIGFBZGEF-UHFFFAOYSA-N VDAOJOKLIXNFRY-UHFFFAOYSA-N CEKMWLSBGRPKES-UHFFFAOYSA-N PTUDVOVIFTXCHK-UHFFFAOYSA-N UXLVGNMLOBCENA-UHFFFAOYSA-N MAHMFPJJKAUVMB-UHFFFAOYSA-N YCGHXWPDGDGPKQ-UHFFFAOYSA-N QFVACMXSSGTRNB-UHFFFAOYSA-N IEDHWPCLYLYTME-UHFFFAOYSA-N LCXPUYSULUUQTQ-UHFFFAOYSA-N OYDTTXUPMJGJQF-UHFFFAOYSA-N GKYYBCNOEUQDTQ-UHFFFAOYSA-N QZVLJNAOIGLPKW-UHFFFAOYSA-N ZIMZHZVDHBTFKS-UHFFFAOYSA-N HPEZANWJRVQQPY-UHFFFAOYSA-N SVYKJBBFRWVRKZ-UHFFFAOYSA-N YJQCLWPGMHGBLU-UHFFFAOYSA-N HHDDKDPLFXIPBX-UHFFFAOYSA-N GUWFEHMMBHOINR-UHFFFAOYSA-N SNVWFSQDKYVAAG-UHFFFAOYSA-N SNWMCNSZCLYXCK-UHFFFAOYSA-N PEJQWNBUKMHGGO-UHFFFAOYSA-N KLIQFVIIBDEFSR-UHFFFAOYSA-N HARUWTIOWZSVJY-UHFFFAOYSA-N NBUAEURVOPSXCJ-UHFFFAOYSA-N VRRHQOVTENICRT-UHFFFAOYSA-N PDVNUOJSRPPQNZ-UHFFFAOYSA-N HEUAVAYKJDRKNK-UHFFFAOYSA-N UGUNGVBWXUEQAQ-UHFFFAOYSA-N GRADMLRLWZORGX-UHFFFAOYSA-N IKSKNYJMDKYTOW-UHFFFAOYSA-N XDKSYOXEWIYWFX-UHFFFAOYSA-N YEGWEZNQGSXHHQ-UHFFFAOYSA-N CFU, colony-forming units hERG (human Ether-a-go-go Related Gene) HPLC, high-performance liquid chromatography LDA, lithium diisopropylamide LiTMP, lithium tetramethylpiperidide LORA, low oxygen recovery assay MABA, microplate alamar blue assay MDR, multidrug-resistant MIC90, minimum concentration for 90% inhibition of growth M. tb, mycobacterium tuberculosis TB, tuberculosis |
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