Xia, Chunnian; Yao, Zhengguang; Xu, Lijuan; Zhang, Wannian; Chen, Haihu; Zhuang, Chunlin published the artcile< Structure-based bioisosterism design of thio-benzoxazepinones as novel necroptosis inhibitors>, Reference of 19346-45-3, the main research area is necroptosis bioisosterism design thiobenzoxazepinones; Bioisosterism; Chirality; Necroptosis; Thio-benzoxazepinone.
Necroptosis is reported to play a critical role in contributing to a variety of human pathologies. The benzoxazepinone GSK′772 is a potent necroptosis inhibitor optimized using a hit from a DNA-encoded library, which is currently in phase II clin. trials for psoriasis, rheumatoid arthritis, and ulcerative colitis. In the present study, the bioisosterism strategy was applied to replace the amide and benzene ring of GSK′772 based on the co-crystal structure of GSK′772 with its binding target RIPK1. As a result, the novel thio-benzoxazepinones exhibited higher anti-necroptosis activity in a human HT-29 cell necroptosis model. The effect on anti-necroptosis activity by the chirality was significantly reduced in the thio-benzoxazepinones, which was explained by the ligand conformation calculation Among these analogs, compound 11 (S) and 12 (R) specifically inhibited necroptosis rather than apoptosis with EC50 values of 2.8 and 22.6 nM. They blocked necrosome formation by inhibiting the phosphorylation of RIPK1, RIPK3 and MLKL in necroptotic cells. Collectively, the highly potent thio-benzoxazepinones represent promising lead structures for further development of necroptosis-related diseases.
European Journal of Medicinal Chemistry published new progress about Cell survival. 19346-45-3 belongs to class pyridine-derivatives, and the molecular formula is C6H5FN2O2, Reference of 19346-45-3.