Nishimura, Nobuko; Norman, Mark H.; Liu, Longbin; Yang, Kevin C.; Ashton, Kate S.; Bartberger, Michael D.; Chmait, Samer; Chen, Jie; Cupples, Rod; Fotsch, Christopher; Helmering, Joan; Jordan, Steven R.; Kunz, Roxanne K.; Pennington, Lewis D.; Poon, Steve F.; Siegmund, Aaron; Sivits, Glenn; Lloyd, David J.; Hale, Clarence; St. Jean, David J. published the artcile< 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>, Recommanded Product: tert-Butyl (5-aminopyridin-2-yl)carbamate, the main research area is arylsulfonamido arylpiperazine glucokinase glucokinase regulatory protein disruptor SAR; AMG 3969 glucokinase glucokinase regulatory protein disruptor SAR; glucose blood level reduction arylsulfonamido arylpiperazine.
We have recently reported a novel approach to increase cytosolic glucokinase (GK) levels through the binding of a small mol. 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 (I, 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 I 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 II and III 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%).
Journal of Medicinal Chemistry published new progress about Antidiabetic agents. 220731-04-4 belongs to class pyridine-derivatives, and the molecular formula is C10H15N3O2, Recommanded Product: tert-Butyl (5-aminopyridin-2-yl)carbamate.