AMG-3969 - CAS 1361224-53-4
Catalog number: B0084-053994
Category: Inhibitor
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AMG-3969 is a potent and selective disruptor of glucokinase-glucokinase regulatory protein interaction (GK-GKRP). AMG-3969 can modulate the blood glucose levels in rodent models of diabetes.
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B0084-053994 100 mg $438 In stock
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1.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.
Nishimura N;Norman MH;Liu L;Yang KC;Ashton KS;Bartberger MD;Chmait S;Chen J;Cupples R;Fotsch C;Helmering J;Jordan SR;Kunz RK;Pennington LD;Poon SF;Siegmund A;Sivits G;Lloyd DJ;Hale C;St Jean DJ Jr J Med Chem. 2014 Apr 10;57(7):3094-116. doi: 10.1021/jm5000497. Epub 2014 Mar 31.
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%).
2.Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles.
St Jean DJ Jr;Ashton KS;Bartberger MD;Chen J;Chmait S;Cupples R;Galbreath E;Helmering J;Hong FT;Jordan SR;Liu L;Kunz RK;Michelsen K;Nishimura N;Pennington LD;Poon SF;Reid D;Sivits G;Stec MM;Tadesse S;Tamayo N;Van G;Yang KC;Zhang J;Norman MH;Fotsch C;Lloyd DJ;Hale C J Med Chem. 2014 Jan 23;57(2):325-38. doi: 10.1021/jm4016747. Epub 2014 Jan 9.
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.
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CAS 1361224-53-4 AMG-3969

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