a-769662 and Diabetes-Mellitus--Type-2

Type 2 diabetes mellitus is a complex metabolic disorder requiring polypharmacology approaches for effective treatment. Combinatorial library of fifteen new tricyclic benzimidazole derivatives have been designed and synthesized to combine fragments commonly found in allosteric AMPK activators and AT

Topics: AMP-Activated Protein Kinases; Animals; Benzimidazoles; Biphenyl Compounds; Cattle; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Enzyme Activators; Glycosylation; Hypoglycemic Agents; Lipopolysaccharides; Macrophages; Mice; Nitric Oxide; Serum Albumin, Bovine; Solubility; Structure-Activity Relationship

A series of novel berberine derivatives, 4,7,12,12a-tetrahydro-5H-thieno[3',2':3,4]pyrido[1,2-b]isoquinolines was designed, synthesized, and biologically evaluated for their anti-diabetic activity. Following the evaluation in two types of cells, compounds 4aa, 4bq, and 4bv stimulated glucose consumption (1.8- to 2.3-fold), reduced gluconeogenesis (60-85%), inhibited mitochondria respiratory chain complex I and activated AMPK indirectly. In a db/db mice model, compounds 4bq and 4bv lowered fasting blood glucose at a dose of 120 mg/kg/day. In addition, compounds 4bq and 4bv were found to possess improved pharmacokinetic profiles (bioavailability 45 and 106%, respectively) compared to berberine. Compounds 4bq and 4bv exhibited no obvious hERG inhibition (IC

Topics: AMP-Activated Protein Kinases; Animals; Carbon-13 Magnetic Resonance Spectroscopy; Cell Line; Diabetes Mellitus, Type 2; Drug Design; Enzyme Activators; Hypoglycemic Agents; Isoquinolines; Mice; Proton Magnetic Resonance Spectroscopy; Rats; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship