2627-52-3Relevant academic research and scientific papers
Further hit optimization of 6-(trifluoromethyl)pyrimidin-2-amine based TLR8 modulators: Synthesis, biological evaluation and structure–activity relationships
Dol?ak, Ana,?ribar, Dora,Scheffler, Alexander,Grabowski, Maria,?vajger, Urban,Gobec, Stanislav,Holze, Janine,Weindl, Günther,Wolber, Gerhard,Sova, Matej
, (2021/09/06)
Toll-like receptor 8 (TLR8) is an endosomal TLR that has an important role in the innate human immune system, which is involved in numerous pathological conditions. Excessive activation of TLR8 can lead to inflammatory and autoimmune diseases, which highlights the need for development of TLR8 modulators. However, only a few small-molecule modulators that selectively target TLR8 have been developed. Here, we report the synthesis and systematic investigation of the structure–activity relationships of a series of novel TLR8 negative modulators based on previously reported 6-(trifluoromethyl)pyrimidin-2-amine derivatives. Four compounds showed low-micromolar concentration-dependent inhibition of TLR8-mediated signaling in HEK293 cells. These data confirm that the 6-trifluoromethyl group and two other substituents on positions 2 and 4 are important structural elements of pyrimidine-based TLR8 modulators. Substitution of the main scaffold at position 2 with a methylsulfonyl group or para hydroxy/hydroxymethyl substituted benzylamine is essential for potent negative modulation of TLR8. Our best-in-class TLR8-selective modulator 53 with IC50 value of 6.2 μM represents a promising small-molecule chemical probe for further optimization to a lead compound with potent immunomodulatory properties.
Discovery of Highly Potent 2-Sulfonyl-Pyrimidinyl Derivatives for Apoptosis Inhibition and Ischemia Treatment
Li, Li,Jiang, Xian,Huang, Shaoqiang,Ying, Zhengxin,Zhang, Zhaolan,Pan, Chenjie,Li, Sisi,Wang, Xiaodong,Zhang, Zhiyuan
supporting information, p. 407 - 412 (2017/04/21)
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.
Synthesis and Metalation of Trifluoromethylpyrimidines. Metalation of Diazines. XVI
Ple, N.,Turck, A.,Heynderickx, A.,Queguiner, G.
, p. 551 - 556 (2007/10/03)
A new route to trifluoromethylpyrimidines is described.Lithiation of trifluoromethylpyrimidines was successfully achieved and was used to synthesize new pyrimidine derivatives.A new synthetic route to a biologically active molecule with antimycotic activi
