55P0110, a Novel Synthetic Compound Developed from a Plant Derived Backbone Structure, Shows Promising Anti-Hyperglycaemic Activity in Mice

Abstract

Starting off with a structure derived from the natural compound multiflorine, a derivatisation program aimed at the discovery and initial characterisation of novel compounds with antidiabetic potential. Design and discovery of the structures was guided by oral bioactivities obtained in oral glucose tolerance tests in mice. 55P0110, one among several new compounds with distinct anti-hyperglycaemic activity, was further examined to characterise its pharmacology and mode of action. Whereas a single oral dose of 55P0110 did not affect basal glycaemia, it markedly improved the glucose tolerance of healthy and diabetic mice (peak blood glucose in glucose tolerance test, mmol/l: healthy mice with 90 mg/kg 55P0110, 17.0±1.2 vs. 10.1±1.1; diabetic mice with 180 mg/kg 55P0110, 23.1±0.9 vs. 11.1±1.4; p<0.001 each). Closer examination argued against retarded glucose resorption from the gut, increased glucose excretion in urine, acute insulin-like or insulin sensitising properties, and direct inhibition of dipeptidyl peptidase-4 as the cause of glucose lowering. Hence, 55P0110 seems to act via a target not exploited by any drug presently approved for the treatment of diabetes mellitus. Whereas the insulinotropic sulfonylurea gliclazide (16 mg/kg) distinctly increased the circulating insulin-per-glucose ratio under basal conditions, 55P0110 (90 mg/kg) lacked such an effect (30 min. after dosing, nmol/mol: vehicle, 2.49±0.27; 55P0110, 2.99±0.35; gliclazide, 8.97±0.49; p<0.001 each vs. gliclazide). Under an exogenous glucose challenge, however, 55P0110 increased this ratio to the same extent as gliclazide (20 min. after glucose feeding: vehicle, 2.53±0.41; 55P0110, 3.80±0.46; gliclazide, 3.99±0.26; p<0.05 each vs. vehicle). By augmenting the glucose stimulated increase in plasma insulin, 55P0110 thus shows distinct anti-hyperglycaemic action in combination with low risk for fasting hypoglycaemia in mice. In summary, we have discovered a novel class of fully synthetic substituted quinazolidines with an attractive pharmacological profile that recommends the structures for further evaluation as candidates for the treatment of diabetes mellitus.

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

“…Standardized OGTTs were performed in mice fasted for 10 hours according to a protocol described previously. 13 In short, the tip of the tail was pricked for measurement of basal blood glucose before the mice received the test compound of interest by gavage (55Pcompounds synthesized at 55pharma's chemistry labs, Tulln, Austria) or the plain vehicle (0.5% sodium carboxymethylcellulose, 5 mL/kg body weight). After another determination of glycaemia 45 minutes later, aqueous glucose solution was administered by gavage (3 g/kg; volume: 6 mL/kg body weight).…”

“…In line with the selected strategy to put weight on disease‐relevant oral activity in vivo , the readout for structural optimization was a standardized oral glucose tolerance test (OGTT) in mice. This led to the discovery of a class of fully synthetic substituted quinazolidines with distinct anti‐hyperglycaemic activity . Initial characterization of one compound, 55P0110, suggested a promising pharmacological profile, including that the acute effect of a single dose outmatched most established oral anti‐diabetic drugs in the mouse OGTT .…”

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

“…Preceding efforts to track down the mechanism(s), which underlie the improvement of glucose tolerance induced by compounds from our derivatization programme, provided evidence for amplification of the glucose‐induced rise in plasma insulin . Glucose‐stimulated insulin release was also enhanced in isolated mouse pancreatic islets exposed to 55P0251 in vitro, suggesting direct effects on islets .…”

“…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).…”

“…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.…”