Global Health R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain.
GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, U.K.
ACS Infect Dis. 2020 May 8;6(5):1098-1109. doi: 10.1021/acsinfecdis.9b00493. Epub 2020 Mar 20.
In the course of optimizing a novel indazole sulfonamide series that inhibits β-ketoacyl-ACP synthase (KasA) of , a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR space against the target ultimately rendered this goal unsuccessful, key structural knowledge around the binding site of this underexplored target for TB was generated to inform future discovery efforts.
在优化新型吲唑磺胺系列以抑制酮酰基-ACP 合酶（KasA）的过程中，发现了一种诱变苯胺代谢物。因此，进一步的先导化合物优化工作致力于通过去除嵌入的苯胺部分或修饰其空间或电子环境来消除这一关键缺陷。尽管针对该靶点的 SAR 空间狭窄，最终未能实现这一目标，但针对结核病这一探索不足的靶点的结合部位生成了关键的结构知识，为未来的发现工作提供了信息。
