Discovery of Highly Potent 2-Sulfonyl-Pyrimidinyl Derivatives for Apoptosis Inhibition and Ischemia Treatment

  • ACS Med Chem Lett. 2017 Mar 1;8(4):407-412. doi: 10.1021/acsmedchemlett.6b00489.
Li Li  1  2 ,  Xian Jiang  2 ,  Shaoqiang Huang  2 ,  Zhengxin Ying  2 ,  Zhaolan Zhang  2 ,  Chenjie Pan  2 ,  Sisi Li  2 ,  Xiaodong Wang  2 ,  Zhiyuan Zhang  2  3
Affiliations
  • 1. School of Life Sciences, Peking University, Beijing 100871, China.
  • 2. National Institute of Biological Sciences (NIBS), Beijing 102206, China.
  • 3. Collaborative Innovation Center for Cancer Medicine, Beijing 102206, China.
PMID: 28435527 DOI: 10.1021/acsmedchemlett.6b00489
Abstract

A series of 2-sulfonyl-pyrimidinyl derivatives was developed as Apoptosis inhibitors. These represent the first class of Apoptosis inhibitors that function through stabilizing mitochondrial respiratory complex II. Starting from a phenotypic screen hit with micromolar activity, we optimized the cellular Apoptosis inhibition activity of 2-sulfonyl-pyrimidinyl derivatives to picomolar level (compound 42, also named as TC9-305). The therapeutic potential of these new Apoptosis inhibitors was further demonstrated by their neuroprotective effect on an ischemic animal model.

Keywords
Apoptosis inhibitors; ischemia treatment; mitochondria protection; phenotypic screen; structure−activity optimization.
Products