Category: chiral-nitrogen-ligands. The reaction of aromatic heterocyclic molecules with protons is called protonation. Aromatic heterocycles are more basic than benzene due to the participation of heteroatoms. Compound: 2-Chloro-5-pyridinesulfonyl chloride, is researched, Molecular C5H3Cl2NO2S, CAS is 6684-39-5, about Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors. Author is Lloyd, David J.; St. Jean, David J. Jr.; Kurzeja, Robert J. M.; Wahl, Robert C.; Michelsen, Klaus; Cupples, Rod; Chen, Michelle; Wu, John; Sivits, Glenn; Helmering, Joan; Komorowski, Renee; Ashton, Kate S.; Pennington, Lewis D.; Fotsch, Christopher; Vazir, Mukta; Chen, Kui; Chmait, Samer; Zhang, Jiandong; Liu, Longbin; Norman, Mark H.; Andrews, Kristin L.; Bartberger, Michael D.; Van, Gwyneth; Galbreath, Elizabeth J.; Vonderfecht, Steven L.; Wang, Minghan; Jordan, Steven R.; Veniant, Murielle M.; Hale, Clarence.
Glucose homeostasis is a vital and complex process, and its disruption can cause hyperglycemia and type II diabetes mellitus. Glucokinase (GK), a key enzyme that regulates glucose homeostasis, converts glucose to glucose-6-phosphate in pancreatic β-cells, liver hepatocytes, specific hypothalamic neurons, and gut enterocytes. In hepatocytes, GK regulates glucose uptake and glycogen synthesis, suppresses glucose production, and is subject to the endogenous inhibitor GK regulatory protein (GKRP). During fasting, GKRP binds, inactivates and sequesters GK in the nucleus, which removes GK from the gluconeogenic process and prevents a futile cycle of glucose phosphorylation. Compounds that directly hyperactivate GK (GK activators) lower blood glucose levels and are being evaluated clin. as potential therapeutics for the treatment of type II diabetes mellitus. However, initial reports indicate that an increased risk of hypoglycemia is associated with some GK activators. To mitigate the risk of hypoglycemia, the authors sought to increase GK activity by blocking GKRP. Here the authors describe the identification of two potent small-mol. GK-GKRP disruptors (AMG-1694 and AMG-3969) that normalized blood glucose levels in several rodent models of diabetes. These compounds potently reversed the inhibitory effect of GKRP on GK activity and promoted GK translocation both in vitro (isolated hepatocytes) and in vivo (liver). A co-crystal structure of full-length human GKRP in complex with AMG-1694 revealed a previously unknown binding pocket in GKRP distinct from that of the phosphofructose-binding site. Furthermore, with AMG-1694 and AMG-3969 (but not GK activators), blood glucose lowering was restricted to diabetic and not normoglycemic animals. These findings exploit a new cellular mechanism for lowering blood glucose levels with reduced potential for hypoglycemic risk in patients with type II diabetes mellitus.
The article 《Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors》 also mentions many details about this compound(6684-39-5)Category: chiral-nitrogen-ligands, you can pay attention to it, because details determine success or failure
Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis