1361224-49-8

Upstream product

• 1228675-25-9 2-oxopiperazine-1,4-dicarboxylic acid 1-tert-butyl ester 4-benzyl ester 
• 16466-97-0 1-propynylmagnesium bromide 
• 501-53-1 benzyl chloroformate 
• 78818-15-2 4-benzyloxycarbonylpiperazin-2-one 

Downstream Products

• 1361224-48-7 2-(4-(4-((6-amino-3-pyridinyl)sulphonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol 
• 1361224-54-5 2-(4-((2R)-4-((6-amino-3-pyridinyl)sulphonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol 
• 1361224-53-4 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulphonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol 
• 1361224-50-1 benzyl 3-(propan-1-yn-1-yl)piperazine-1-carboxylate 
• 1361224-51-2 benzyl 3-(1-propyn-1-yl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-phenyl)-1-piperazinecarboxylate 
• 1361224-52-3 2-(4-(4-((6-chloro-3-pyridinyl)sulphonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol 
• 1361224-72-7 1,1,1,3,3,3-hexafluoro-2-(4-(2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol 
• 1361221-40-0 1,1,1,3,3,3-hexafluoro-2-(4-(4-(phenylsulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol 
• 1388234-62-5 2-(4-(4-((1,3-thiazol-2-yl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol 
• 1361224-80-7 2-(4-(4-((6-amino-5-fluoro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol 
• 1361224-81-8 2-(4-(4-((6-chloro-5-fluoro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol 
• 1589534-97-3 5-(((3S)-4-(4-(methylsulfinyl)phenyl)-3-(1-propyn-1-yl)-1-piperazinyl)sulfonyl)-2-pyridinamine 
• 1589534-95-1 tert-butyl (5-(((3S)-4-(4-(methylcarbamoyl)phenyl)-3-(1-propyn-1-yl)-1-piperazinyl)sulfonyl)-2-pyridinyl)carbamate 
• 1589534-94-0 N-methyl-4-((2S)-2-(1-propyn-1-yl)-1-piperazinyl)benzamide 

Relevant academic research and scientific papers

Novel RET inhibitors. Pharmaceutical composition and use thereof

The invention belongs to the field of medicines, and relates to a novel RET inhibitor, a pharmaceutical composition and application thereof. , The present invention relates to a compound represented by formula (I), a stereoisomer, a tautomer, an oxynitrid

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.

TRICYCLIC ALKYNES THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN

The present invention relates to tricyclic alkyne compounds of formula I 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 gluco

Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 3. Structure-activity relationships within the aryl carbinol region of the N-arylsulfonamido-N′-arylpiperazine series

We have recently reported a novel approach to increase cytosolic glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, glucokinase regulatory protein (GKRP) these initial investigations culminated in the identification of 2-(4-((2S)-4-((6-amino-3- pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3, 3-hexafluoro-2-propanol (1, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound 1 bound to hGKRP, we identified several potent GK-GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives 24 and 29 possessed excellent potency as well as favorable PK properties. When dosed orally in db/db mice, both compounds significantly lowered fed blood glucose levels (up to 58%).

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.

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.

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.