Journal of Medicinal Chemistry p. 5293 - 5305 (2014)
Update date:2022-08-15
Topics:
Kang, Sunhee
Kim, Ryang Yeo
Seo, Min Jung
Lee, Saeyeon
Kim, Young Mi
Seo, Mooyoung
Seo, Jeong Jea
Ko, Yoonae
Choi, Inhee
Jang, Jichan
Nam, Jiyoun
Park, Seijin
Kang, Hwankyu
Kim, Hyung Jun
Kim, Jungjun
Ahn, Sujin
Pethe, Kevin
Nam, Kiyean
No, Zaesung
Kim, Jaeseung
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 log10 reduction at 10 mg/kg dosing level, respectively) in mouse lung.
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