1361224-53-4

Usage

Uses

Used in Pharmaceutical Industry:
AMG-3969 is used as an antidiabetic agent for the treatment of type II diabetes. It functions by disrupting the GK-GKRP interaction, which leads to an increase in GK translocation and, consequently, a reduction in blood glucose levels. This mechanism of action presents a potential advantage over traditional diabetes treatments, as it may lower the risk of hypoglycemic events.
Additionally, given its specific mode of action, AMG-3969 could be used as a research tool in the study of GK-GKRP interactions and their role in glucose homeostasis, potentially leading to the development of other novel therapeutics for diabetes management.

References

Lloyd, David J., et al. "Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors." Nature 504.7480(2013):437-40. Bourbeau, M. P., et al. "Nonracemic synthesis of GK-GKRP disruptor AMG-3969. " Synfacts 79.8(2014):3684. http://www.metonchem.com/products/amg-3969-cas1361224-53-4/

Upstream product

• 1450620-16-2 tert-butyl (5-(chlorosulfonyl)-2-pyridinyl)carbamate 
• 1450620-19-5 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol 
• 1450621-79-0 (3S)-1-benzyl-3-(2-propyn-1-yl)-piperazine 
• 1450621-80-3 2-(4-((2S)-4-benzyl-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol 
• 1572928-68-7 tert-butyl (5-(((3S)-3-(1-propyn-1-yl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinyl)sulfonyl)-2-pyridinyl)carbamate 
• 1450620-25-3 (3S)-1-benzyl-3-(1-propyn-1-yl)piperazine 
• 220731-04-4 5-amino-2-tert-butyloxycarbonylaminopyridine 
• 1450621-78-9 (3S)-1-benzyl-3-(2-propyn-1-yl)-2,5-piperazinedione 
• 1361224-50-1 benzyl 3-(propan-1-yn-1-yl)piperazine-1-carboxylate 
• 1361224-49-8 benzyl (2-((tert-butoxycarbonyl)amino)ethyl)(2-oxo-3-pentyn-1-yl)-carbamate 
• 1526937-49-4 C₂₁H₁₈ClF₆N₃O₃S 
• 1450620-20-8 benzyl (3S)-3-(1-propyn-1-yl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate 
• 289483-92-7 6-Amino-3-pyridinesulfonyl Chloride 
• 1361224-72-7 1,1,1,3,3,3-hexafluoro-2-(4-(2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol 

Downstream Products

• 1450621-61-0 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-((1Z)-1-propen-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol 

Relevant academic research and scientific papers

Nonracemic synthesis of GK-GKRP disruptor AMG-3969

A nonracemic synthesis of the glucokinase-glucokinase regulatory protein disruptor AMG-3969 (5) is reported. Key features of the synthetic approach are an asymmetric synthesis of the 2-alkynyl piperazine core via a base-promoted isomerization and a revised approach to the synthesis of the aminopyridinesulfonamide with an improved safety profile.

Small molecule disruptors of the Glucokinase-Glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles

In the previous report, we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of 1 (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (27, AMG-3969). When administered to db/db mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels.

SULFONYL COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN

The present invention relates to sulfonyl compounds that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.

Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors

Glucose homeostasis is a vital and complex process, and its disruption can cause hyperglycaemia 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 clinically as potential therapeutics for the treatment of type II diabetes mellitus. However, initial reports indicate that an increased risk of hypoglycaemia is associated with some GK activators. To mitigate the risk of hypoglycaemia, we sought to increase GK activity by blocking GKRP. Here we describe the identification of two potent small-molecule 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 normoglycaemic animals. These findings exploit a new cellular mechanism for lowering blood glucose levels with reduced potential for hypoglycaemic risk in patients with type II diabetes mellitus.

SULFONYLPIPERAZINE DERIVATIVES THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN FOR THE TREATMENT OF DIABETES

The present invention relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.