Preclinical characterization of 55P0251, a novel compound that amplifies glucose‐stimulated insulin secretion and counteracts hyperglycaemia in rodents

Abstract

55P0251 is a novel compound that potently counteracts hyperglycaemia in rodents via amplification of glucose-stimulated insulin release.

Evidence that the multiflorine‐derived substituted quinazolidine 55P0251 augments insulin secretion and lowers blood glucose via antagonism at α2‐adrenoceptors in mice

“…Oral glucose tolerance tests (OGTTs) were performed in mice fasted for ~10 hours and were performed according to a standard protocol described previously . In short, the tip of the tail was pricked and basal blood glucose was measured in duplicate with a portable glucose meter (OneTouch; LifeScan, Milpitas, California).…”

“…In rodents, 55P0251 exhibited attractive anti‐hyperglycaemic, but not hypoglycaemic action, which could be attributed to augmentation of glucose‐stimulated insulin secretion via a molecular mechanism that differed from those addressed by drugs currently in use for the treatment of diabetes mellitus. No evidence was found for an extrapancreatic mechanism contributing to the lowering of blood glucose . Based on several experimental approaches, including comparison to promising candidates that were discovered later than 55P0251, we here report further efforts to pin down the molecular target and the mechanisms responsible for blood glucose‐lowering.…”

“…Based on work from Kubo et al, who described multiflorine derivatives with antidiabetic properties in mice, we used a molecular scaffold derived from (−)‐multiflorine as the starting point for an extensive derivatization programme. In line with the idea of building on bioactivity in vivo, we used glucose tolerance tests in orally dosed mice for structural optimization and discovered a novel class of fully synthetic substituted quinazolidines with distinct anti‐hyperglycaemic activity . Structural development based on oral administration and a disease‐relevant endpoint allows selection for distinctive acute side effects, solubility, formulation properties and bioavailability at the earliest possible stage.…”

“…Encouraged by this outcome, we continued our efforts, resulting in the development of numerous active derivatives, from which 55P0251 was selected for detailed examination. 55P0251 is a further‐refined structure, which carries superior efficacy in comparison to 55P0110 accompanied by attractive pharmacokinetic attributes . In rodents, 55P0251 exhibited attractive anti‐hyperglycaemic, but not hypoglycaemic action, which could be attributed to augmentation of glucose‐stimulated insulin secretion via a molecular mechanism that differed from those addressed by drugs currently in use for the treatment of diabetes mellitus.…”

Life Under Hypoxia Lowers Blood Glucose Independently of Effects on Appetite and Body Weight in Mice

“…The GTT and the ITT were performed along protocols employed earlier (30, 31). In the GTT, blood glucose was measured in mice fasted for 8 h and immediately thereafter, glucose solution was injected intraperitoneally (1.5 g/kg; 4.5 ml/kg).…”