91013-21-7Relevant academic research and scientific papers
Variations in the C-unit of bedaquiline provides analogues with improved biology and pharmacology
Blaser, Adrian,Choi, Peter J.,Cooper, Christopher B.,Denny, William A.,Franzblau, Scott G.,Lotlikar, Manisha,Palmer, Brian D.,Sutherland, Hamish S.,Tong, Amy S. T.,Upton, Anna M.
, (2020)
Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3,5-dimethoxy-4-pyridyl C-unit, retain high anti-bacterial potency yet exert less inhibition of the hERG potassium channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3,5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.16 to 1.89). This broader class shows similar properties to the 3,5-dimethoxy-4-pyridyl series, being substantially more potent in vitro and equally active in an in vivo (mouse) model than bedaquiline, while retaining a lower cardiovascular risk profile through greatly attenuated hERG inhibition.
Structure-activity relationships for unit C pyridyl analogues of the tuberculosis drug bedaquiline
Blaser, Adrian,Sutherland, Hamish S.,Tong, Amy S.T.,Choi, Peter J.,Conole, Daniel,Franzblau, Scott G.,Cooper, Christopher B.,Upton, Anna M.,Lotlikar, Manisha,Denny, William A.,Palmer, Brian D.
, p. 1283 - 1291 (2019/02/24)
The ATP-synthase inhibitor bedaquiline is effective against drug-resistant tuberculosis but is extremely lipophilic (clogP 7.25) with a very long plasma half-life. Additionally, inhibition of potassium current through the cardiac hERG channel by bedaquiline, is associated with prolongation of the QT interval, necessitating cardiovascular monitoring. Analogues were prepared where the naphthalene C-unit was replaced with substituted pyridines to produce compounds with reduced lipophilicity, anticipating a reduction in half-life. While there was a direct correlation between in vitro inhibitory activity against M. tuberculosis (MIC90) and compound lipophilicity, potency only fell off sharply below a clogP of about 4.0, providing a useful lower bound for analogue design. The bulk of the compounds remained potent inhibitors of the hERG potassium channel, with notable exceptions where IC50 values were at least 5-fold higher than that of bedaquiline. Many of the compounds had desirably higher rates of clearance than bedaquiline, but this was associated with lower plasma exposures in mice, and similar or higher MICs resulted in lower AUC/MIC ratios than bedaquiline for most compounds. The two compounds with lower potency against hERG exhibited similar clearance to bedaquiline and excellent efficacy in vivo, suggesting further exploration of C-ring pyridyls is worthwhile.
Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles
Sutherland, Hamish S.,Tong, Amy S.T.,Choi, Peter J.,Conole, Daniel,Blaser, Adrian,Franzblau, Scott G.,Cooper, Christopher B.,Upton, Anna M.,Lotlikar, Manisha U.,Denny, William A.,Palmer, Brian D.
, p. 1797 - 1809 (2018/02/28)
Replacing the naphthalene C-unit of the anti-tuberculosis drug bedaquiline with a range of bicyclic heterocycles of widely differing lipophilicity gave analogs with a 4.5-fold range in clogP values. The biological results for these compounds indicate on average a lower clogP limit of about 5.0 in this series for retention of potent inhibitory activity (MIC90s) against M.tb in culture. Some of the compounds also showed a significant reduction in inhibition of hERG channel potassium current compared with bedaquiline, but there was no common structural feature that distinguished these.
ANTIBACTERIAL COMPOUNDS AND USES THEREOF
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Paragraph 0212, (2017/09/28)
The present invention relates to compounds of formula (I) including any stereochemically isomeric form thereof, or pharmaceutically acceptable salts thereof, for the treatment of tuberculosis.
