- Rh(iii)-Catalyzed diastereoselective transfer hydrogenation: An efficient entry to key intermediates of HIV protease inhibitors
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A highly efficient diastereoselective transfer hydrogenation of α-aminoalkyl α′-chloromethyl ketones catalyzed by a tethered rhodium complex was developed and successfully utilized in the synthesis of the key intermediates of HIV protease inhibitors. With the current Rh(iii) catalyst system, a series of chiral 3-amino-1-chloro-2-hydroxy-4-phenylbutanes were produced in excellent yields and diastereoselectivities (up to 99% yield, up to 99?:?1 dr). Both diastereomers of the desired products could be efficiently accessed by using the two enantiomers of the Rh(iii) catalyst.
- Chen, Gen-Qiang,Lang, Qi-Wei,Phansavath, Phannarath,Ratovelomanana-Vidal, Virginie,Wang, Fangyuan,Wu, Ting,Yin, Congcong,Zhang, Xumu,Zheng, Long-Sheng
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supporting information
p. 3119 - 3122
(2020/03/23)
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- Small molecule disruptors of the Glucokinase-Glucokinase regulatory protein interaction: 1. Discovery of a novel tool compound for in vivo proof-of-concept
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Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enzyme. Herein we report the identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket. Using a structure-based approach, the potency of the initial hit was improved to provide 25 (AMG-1694). When dosed in ZDF rats, 25 showed both a robust pharmacodynamic effect as well as a statistically significant reduction in glucose. Additionally, hypoglycemia was not observed in either the hyperglycemic or normal rats.
- Ashton, Kate S.,Andrews, Kristin L.,Bryan, Marion C.,Chen, Jie,Chen, Kui,Chen, Michelle,Chmait, Samer,Croghan, Michael,Cupples, Rod,Fotsch, Christopher,Helmering, Joan,Jordan, Steve R.,Kurzeja, Robert J. M.,Michelsen, Klaus,Pennington, Lewis D.,Poon, Steve F.,Sivits, Glenn,Van, Gwyneth,Vonderfecht, Steve L.,Wahl, Robert C.,Zhang, Jiandong,Lloyd, David J.,Hale, Clarence,St. Jean, David J.
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p. 309 - 324
(2014/02/14)
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