88982-82-5Relevant articles and documents
Process Development of a Second Generation β-Amyloid-Cleaving Enzyme Inhibitor - Improving the Robustness of a Halogen-Metal Exchange Using Continuous Stirred-Tank Reactors
Li, Bryan,Barnhart, Richard W.,Dion, Amelie,Guinness, Steven,Happe, Alan,Hayward, Cheryl M.,Kohrt, Jeffrey,Makowski, Teresa,Maloney, Mark,Nelson, Jade D.,Nematalla, Asaad,McWilliams, J. Christopher,Peng, Zhihui,Raggon, Jeffrey,Sagal, John,Weisenburger, Gerald A.,Bao, Denghui,Gonzalez, Miguel,Lu, Jiangping,McLaws, Mark D.,Tao, Jian,Wu, Baolin
, p. 1440 - 1453 (2021/06/21)
Process development for the synthesis of a second generation β-amyloid-cleaving enzyme (BACE1) inhibitor (1) is described. The lithiothiazole addition to the isoxazolene (5) under batch conditions was not scalable because of reaction gelling and anion instability. A continuous stirred-tank reactor flow process was developed and successfully executed on the 70 kg scale in multiple runs. In a head-to-head comparison between the continuous and batch processes, the former was clearly superior as it gave a higher yield (80 vs 63%) of the adduct (4) and better reaction control for handling the unstable lithiothiazole as a reaction intermediate. Subsequently, 4 underwent Pd-catalyzed amination with t-butyl carbamate, reductive cleavage of the N-O bond, thioamidine cyclization, and deprotection of the Boc group to provide hydropyranothiazine 2. The synthesis of 1 was completed by amidation with 5-(difluoromethoxy)picolinic acid and the successive deprotection of the benzamide group with either Silicycle-diamine or l-lysine.
Discovery, Structure-Activity Relationship, and Biological Activity of Histone-Competitive Inhibitors of Histone Acetyltransferases P300/CBP
Wu, Fangrui,Hua, Yuanda,Kaochar, Salma,Nie, Shenyou,Lin, Yi-Lun,Yao, Yuan,Wu, Jingyu,Wu, Xiaowei,Fu, Xiaoyong,Schiff, Rachel,Davis, Christel M.,Robertson, Matthew,Ehli, Erik A.,Coarfa, Cristian,Mitsiades, Nicholas,Song, Yongcheng
, p. 4716 - 4731 (2020/05/05)
Histone acetyltransferase (HAT) p300 and its paralog CBP acetylate histone lysine side chains and play critical roles in regulating gene transcription. The HAT domain of p300/CBP is a potential drug target for cancer. Through compound screening and medicinal chemistry, novel inhibitors of p300/CBP HAT with their IC50 values as low as 620 nM were discovered. The most potent inhibitor is competitive against histone substrates and exhibits a high selectivity for p300/CBP. It inhibited cellular acetylation and had strong activity with EC50 of 1-3 μM against proliferation of several tumor cell lines. Gene expression profiling in estrogen receptor (ER)-positive breast cancer MCF-7 cells showed that inhibitor treatment recapitulated siRNA-mediated p300 knockdown, inhibited ER-mediated gene transcription, and suppressed expression of numerous cancer-related gene signatures. These results demonstrate that the inhibitor is not only a useful probe for biological studies of p300/CBP HAT but also a pharmacological lead for further drug development targeting cancer.
Synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as mGluR5 (metabotropic glutamate receptor 5) antagonists
Vu, Hoang Nam,Kim, Ji Young,Hassan, Ahmed H.E.,Choi, Kihang,Park, Jong-Hyun,Park, Ki Duk,Lee, Jae Kyun,Pae, Ae Nim,Choo, Hyunah,Min, Sun-Joon,Cho, Yong Seo
supporting information, p. 140 - 144 (2015/12/18)
We described here the synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as potential mGluR5 antagonists. We found that a series of thiazole derivatives 6 showed better inhibitory activity against mGluR5. Compounds 6bc and 6bj have been identified as potent antagonists (IC50 = 274 and 159 nM) showing excellent in vitro stability profile. Molecular docking study using the crystal structure of mGluR5 revealed that our compounds 6bc and 6bj fit the allosteric binding site of mavoglurant well.
