ATx09-002 / Astellas, Alanza - LARVOL DELTA

Discovery and Activity Evaluation of Novel Dibenzoxazepinone Derivatives as Glycogen Phosphorylase Inhibitors. (PubMed, Molecules) - "The in vitro activity screening results indicated that compound Id most significantly inhibited glycogen phosphorylase (GP) activity, with an IC50 of 266 ± 1 nM, which was superior to the positive control drug PSN-357, a Phase II clinical GP inhibitor from Japan's OSI Corporation. In vivo experiments showed that Id could significantly reduce blood glucose levels in adrenaline-induced acute hyperglycemic mice and high-fat-diet-induced obese and diabetic (DIO) mice."

Journal • Diabetes • Metabolic Disorders • Obesity

Synthesis and Activity Evaluation of Novel Benzoxazepinone Derivatives as Potential Inhibitors of Glycogen Phosphorylase. (PubMed, Molecules) - "Its inhibition of glycogen degradation in HL-7702 cells was three times greater than that of PSN-357. Molecular docking studies revealed that the binding conformation of compound 8g with PYGL allowed the benzoxazinone moiety to form stable hydrogen-bond networks and hydrophobic interactions, which may explain its excellent activity."

Journal • PYGL

Discovery of novel heterocyclic derivatives as potential glycogen phosphorylase inhibitors with a cardioprotective effect. (PubMed, Bioorg Chem) - "In particular, compound IIIh (IC = 0.21 ± 0.03 µM) emerged as a potent derivative against RMGPa, being approximately 2-fold less potent than that of PSN-357...Besides, in vivo activity evaluation demonstrated that compound IIIh exhibited obviously cardioprotective effect on MI/R injury mice. The discovery of compound IIIh provides a new strategy for developing novel GP inhibitors with myocardial ischemia protection."

Journal • Cardiovascular • Myocardial Ischemia

Novel Liver-targeted conjugates of Glycogen Phosphorylase Inhibitor PSN-357 for the Treatment of Diabetes: Design, Synthesis, Pharmacokinetic and Pharmacological Evaluations. (PubMed) - Sci Rep - "In the in vivo animal study of hypoglycemia under the same dose of 50 mg/kg, conjugate 6 exhibited a small but significant hypoglycemic effects in longer-acting manners, that the hypoglycemic effects of 6 is somewhat weaker than PSN-357 from administration up to 6 h, and then became higher than PSN-357 for the rest time of the test. Those results indicate that the liver-targeted glycogen phosphorylase inhibitor may hold utility in the treatment of type 2 diabetes."

Journal • Biosimilar • Diabetes