期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 12, 页码 5293-5305出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm5003606
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资金
- National Research Foundation of Korea (NRF) - Korean government (MSIP) [2007-00559]
- Gyeonggi-do
- Qurient Inc.
- KISTI
- National Research Foundation of Korea [KDDF-201302-01, 2007-00559] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
A critical unmet clinical need to combat the global tuberculosis epidemic is the development of potent agents capable of reducing the time of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis therapy. In this paper, we report on the optimization of imidazo[1,2-a]pyridine amide (IPA) lead compound 1, which led to the design and synthesis of Q203 (50). We found that the amide linker with IPA core is very important for activity against Mycobacterium tuberculosis H37Rv. Linearity and lipophilicity of the amine part in the IPA series play a critical role in improving in vitro and in vivo efficacy and pharmacokinetic profile. The optimized IPAs 49 and 50 showed not only excellent oral bioavailability (80.2% and 90.7%, respectively) with high exposure of the area under curve (AUC) but also displayed significant colony-forming unit (CFU) reduction (1.52 and 3.13 log(10) reduction at 10 mg/kg dosing level, respectively) in mouse lung.
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