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

Autor: Mark H. Norman, Nobuko Nishimura, Samer Chmait, Rod Cupples, Kate Ashton, Roxanne Kunz, Joan Helmering, Aaron C. Siegmund, David J. St. Jean, Clarence Hale, David Lloyd, Steven R. Jordan, Glenn Sivits, Michael D. Bartberger, Christopher H. Fotsch, Kevin Yang, Steve F. Poon, Lewis D. Pennington, Longbin Liu, Jie Chen
Rok vydání: 2014
Předmět:
Zdroj: Journal of medicinal chemistry. 57(7)
ISSN: 1520-4804
Popis: 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%).
Databáze: OpenAIRE