期刊
MOLECULES
卷 25, 期 6, 页码 -出版社
MDPI
DOI: 10.3390/molecules25061423
关键词
bedaquiline; TMC207; Sirturo; bedaquiline analogues; TBAJ-876; mycobacterium tuberculosis; tuberculosis; drug development
资金
- Bill AMP
- Melinda Gates Foundation [OPP1017459]
- U.S. Agency for International Development (USAID)
- U.K. Department for International Development (DFID)
- Directorate General for International Cooperation of the Netherlands (DGIS)
- Irish Aid
- Bill and Melinda Gates Foundation [OPP1017459] Funding Source: Bill and Melinda Gates Foundation
Bedaquiline is a novel drug approved in 2012 by the FDA for treatment of drug-resistant tuberculosis (TB). Although it shows high efficacy towards drug-resistant forms of TB, its use has been limited by the potential for significant side effects. In particular, bedaquiline is a very lipophilic compound with an associated long terminal half-life and shows potent inhibition of the cardiac potassium hERG channel, resulting in QTc interval prolongation in humans that may result in cardiac arrhythmia. To address these issues, we carried out a drug discovery programme to develop an improved second generation analogue of bedaquiline. From this medicinal chemistry program, a candidate (TBAJ-876) has been selected to undergo further preclinical evaluation. During this evaluation, three major metabolites arising from TBAJ-876 were observed in several preclinical animal models. We report here our synthetic efforts to unequivocally structurally characterize these three metabolites through their independent directed synthesis.
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