Klabunde, Thomas published the artcileAcyl Ureas as Human Liver Glycogen Phosphorylase Inhibitors for the Treatment of Type 2 Diabetes, Computed Properties of 2447-79-2, the publication is Journal of Medicinal Chemistry (2005), 48(20), 6178-6193, database is CAplus and MEDLINE.
Using a focused screening approach, acyl ureas have been discovered as a new class of inhibitors of human liver glycogen phosphorylase (hlGPa). The x-ray structure of screening hit 1 (IC50 = 2 μM) in a complex with rabbit muscle glycogen phosphorylase b reveals that 1 binds at the AMP site, the main allosteric effector site of the dimeric enzyme. A first cycle of chem. optimization supported by x-ray structural data yielded derivative 21, which inhibited hlGPa with an IC50 of 23±1 nM, but showed only moderate cellular activity in isolated rat hepatocytes (IC50 = 6.2 μM). Further optimization was guided by (i) a 3D pharmacophore model that was derived from a training set of 24 compounds and revealed the key chem. features for the biol. activity and (ii) the 1.9 Å crystal structure of 21 in complex with hlGPa. A second set of compounds was synthesized and led to 42 with improved cellular activity (hlGPa IC50 = 53±1 nM; hepatocyte IC50 = 380 nM). Administration of 42 to anesthetized Wistar rats caused a significant reduction of the glucagon-induced hyperglycemic peak. These findings are consistent with the inhibition of hepatic glycogenolysis and support the use of acyl ureas for the treatment of type 2 diabetes.
Journal of Medicinal Chemistry published new progress about 2447-79-2. 2447-79-2 belongs to amides-buliding-blocks, auxiliary class Chloride,Amine,Benzene,Amide, name is 2,4-Dichlorobenzamide, and the molecular formula is C7H5Cl2NO, Computed Properties of 2447-79-2.
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