4OHM: Human Gkrp Bound To Amg-0771 And Sorbitol-6-phosphate

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%).
PDB ID: 4OHMDownload
MMDB ID: 121911
PDB Deposition Date: 2014/1/17
Updated in MMDB: 2014/10
Experimental Method:
x-ray diffraction
Resolution: 2.4  Å
Source Organism:
Similar Structures:
Biological Unit for 4OHM: monomeric; determined by author and by software (PISA)
Molecular Components in 4OHM
Label Count Molecule
Protein (1 molecule)
Glucokinase Regulatory Protein(Gene symbol: GCKR)
Molecule annotation
Chemicals (13 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB