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

PLoS One. 2015 May 14;10(5):e0126847. doi: 10.1371/journal.pone.0126847. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Area Under Curve
  • Blood Glucose / analysis
  • Blood Glucose / drug effects*
  • Diabetes Mellitus, Experimental / drug therapy
  • Dipeptidyl Peptidase 4 / chemistry
  • Dipeptidyl Peptidase 4 / metabolism
  • Glucose Tolerance Test
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Insulin / blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Quinolizines / chemistry*
  • Quinolizines / pharmacology
  • Quinolizines / therapeutic use
  • ROC Curve

Substances

  • 55P0110
  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Quinolizines
  • Dipeptidyl Peptidase 4
  • Dpp4 protein, mouse

Grants and funding

This work was supported by The Austrian Research Promotion Agency (https://www.ffg.at/en; Grant No. BRIDGE 812095-SCK/SAI to BB). This funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. "55pharma Drug Discovery & Development AG" provided additional support in the form of salaries for authors IA, KF, and LB and consultancy fees for CF, but did not have a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of authors are articulated in the "author contributions" section.