Abstract
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.
Highlights
Bedaquiline (TMC207, Sirturo, Janssen Pharmaceuticals; Fig. 1; 1) is an exciting new drug for tuberculosis, with a novel mechanism of inhibition of the mycobacterial ATP synthase.1 Of particular interest, it has demonstrated clinical efficacy against multidrug-resistant TB, where treatment options are limited.2 Potential limitations of 1 include very high lipophilicity,3 with the attendant risks of ultra-long half-life,4 phospholipidosis,5 and drug insolubility
Against Mycobacterium tuberculosis, but with lower lipophilicity than bedaquiline, anticipating a desirably shorter half-life, we have recently reported on the beneficial effects of replacing the lipophilic 6-Br group on the A-unit quinoline ring with a more hydrophilic cyano group,6 replacing the B-unit phenyl group with monoheterocycles,7 and replacing the very lipophilic C-unit naphthalene with a series of less lipophilic bicyclic heterocycles
Lithium tetramethylpiperidide (LiTMP) mediated condensation of quinoline A and substituted benzaldehydes B gave the intermediate alcohols, which were deoxygenated by triethylsilane under acid conditions to give the corresponding A/B units
Summary
Bedaquiline (TMC207, Sirturo, Janssen Pharmaceuticals; Fig. 1; 1) is an exciting new drug for tuberculosis, with a novel mechanism of inhibition of the mycobacterial ATP synthase. Of particular interest, it has demonstrated clinical efficacy against multidrug-resistant TB, where treatment options are limited. Potential limitations of 1 include very high lipophilicity (a calculated clogP of 7.25), with the attendant risks of ultra-long half-life, phospholipidosis, and drug insolubility. Bedaquiline (TMC207, Sirturo, Janssen Pharmaceuticals; Fig. 1; 1) is an exciting new drug for tuberculosis, with a novel mechanism of inhibition of the mycobacterial ATP synthase.. Bedaquiline (TMC207, Sirturo, Janssen Pharmaceuticals; Fig. 1; 1) is an exciting new drug for tuberculosis, with a novel mechanism of inhibition of the mycobacterial ATP synthase.1 Of particular interest, it has demonstrated clinical efficacy against multidrug-resistant TB, where treatment options are limited.. Against Mycobacterium tuberculosis, but with lower lipophilicity than bedaquiline, anticipating a desirably shorter half-life, we have recently reported on the beneficial effects of replacing the lipophilic 6-Br group on the A-unit quinoline ring with a more hydrophilic cyano group, replacing the B-unit phenyl group with monoheterocycles, and replacing the very lipophilic C-unit naphthalene with a series of less lipophilic bicyclic heterocycles.. The only other study on non-naphthalene analogues of 1 showed that 2fluoro- and 2,5-difluorophenyl compounds had MIC90 values (in Mycobacterium smegmatis) comparable to that of 1, but pyridyl analogues were not examined
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