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 |
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| Rok vydání: | 2014 |
| Předmět: |
Blood Glucose
Models Molecular Stereochemistry Biological Availability Stereoisomerism Crystallography X-Ray Piperazines chemistry.chemical_compound Mice Structure-Activity Relationship Drug Discovery Glucokinase Diabetes Mellitus Structure–activity relationship Animals Hypoglycemic Agents Sulfonyl chemistry.chemical_classification Sulfonamides Glucokinase regulatory protein biology Aryl Small molecule Rats Disease Models Animal chemistry Biochemistry Microsome biology.protein Hepatocytes Microsomes Liver Molecular Medicine Carrier Proteins |
| 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 |
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