Clark Michael P, Wang Tiansheng, Perola Emanuele, Deininger David D, Zuccola Harmon J, Jones Steven M, Gao Hong, VanderVen Brian C, Russell David G, Shoen Carolyn M, Cynamon Michael H, Thomson John A, Locher Christopher P
Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA.
Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA.
Bioorg Med Chem Lett. 2017 Sep 1;27(17):3987-3991. doi: 10.1016/j.bmcl.2017.07.067. Epub 2017 Jul 27.
To develop agents for the treatment of infections caused by Mycobacterium tuberculosis, a novel phenotypic screen was undertaken that identified a series of 2-N-aryl thiazole-based inhibitors of intracellular Mycobacterium tuberculosis. Analogs were optimized to improve potency against an attenuated BSL2 H37Ra laboratory strain cultivated in human macrophage cells in vitro. The insertion of a carboxylic acid functionality resulted in compounds that retained potency and greatly improved microsomal stability. However, the strong potency trends we observed in the attenuated H37Ra strain were inconsistent with the potency observed for virulent strains in vitro and in vivo.
为开发用于治疗结核分枝杆菌引起感染的药物，我们进行了一项新型表型筛选，鉴定出一系列基于2-N-芳基噻唑的细胞内结核分枝杆菌抑制剂。对类似物进行了优化，以提高其对在人巨噬细胞中体外培养的减毒BSL2 H37Ra实验室菌株的效力。引入羧酸官能团得到的化合物保留了效力并大大提高了微粒体稳定性。然而，我们在减毒H37Ra菌株中观察到的强效趋势与在体外和体内对有毒菌株观察到的效力不一致。
