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

<div><p>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.</p></div

No direct effect of novel compounds on DPP-4 activity in vitro.

<p>Direct effects of 0.1, 1, or 10 μmol/l 55P0104, 55P0108, 55P0110, or an established DPP-4 inhibitor as provided by the assay manufacturer on DPP-4 activity in vitro. Substrate conversion measured at least in duplicate at 5 min intervals over 60 min.</p

55P0001 initially reduces, but later elevates blood glucose during a glucose tolerance test in mice.

<p>Male C57BL/6J mice were intraperitoneally injected with 10 mg/kg (left) or 50 mg/kg (right) 55P0001 (solid lines), or with the vehicle (broken lines) immediately before an oral glucose tolerance test (3 g/kg). The insert shows the chemical structure of 55P0001. Means±SEM; n = 11 each; *p<0.05, †p<0.001 vs. vehicle.</p

A single dose of 55P0110 improves glucose tolerance but not insulin sensitivity in diabetic mice.

<p>Effect of feeding 180 mg/kg 55P0110 to 9 weeks-old (<b>A</b>) or 90 mg/kg 55P0110 to 12 weeks-old (<b>B</b>) fasted male db/db mice at -45 min before an oral glucose tolerance test (2 g/kg). Glucose curve and incremental area under the glucose curve (AUCinc) are shown. (<b>C</b>) Effect of feeding 90 mg/kg 55P0110 at -45 min on an insulin tolerance test (1.5 U/kg) in 14 weeks-old male db/db mice. 55P0110, full lines; vehicle, broken lines; means±SEM; n = 9–10 each; *p<0.05; †p<0.01; ‡p<0.001 vs. vehicle.</p

Improvement of glucose tolerance by 55P0110 is independent of the route of administration.

<p>Effects of 90 mg/kg 55P0110 (full lines) as compared to vehicle (broken lines) on glucose excursion and incremental area under the glucose curve (AUCinc) in intraperitoneal glucose tolerance tests (2 g/kg) in male C57BL/6J mice. (<b>A</b>) Glucose injected 45 min after oral administration of 55P0110. (<b>B</b>) Glucose injected 15 min after intraperitoneal injection of 55P0110. Means±SEM; n = 7–9 each; *p<0.05; †p<0.01; ‡p<0.001 vs. vehicle.</p

Novel compounds that dose-dependently improve glucose tolerance in mice.

<p>The indicated doses of novel compounds (codes and chemical structures shown above the bar graphs) were orally administered to male C57BL/6J mice 45 min before a standard oral glucose tolerance test was started (3 g/kg). Effects on the total area under the glucose curve (AUC; <b>A</b>), and on the peak increment in blood glucose 30 min after glucose administration (<b>B</b>) are given as % of mean values of the corresponding vehicle group. Means±SEM; n = 6–16 each; *p<0.05; †p<0.01; ‡p<0.001 vs. vehicle (= 100%; open bars).</p

Comparison of 55P0110 to established anti-diabetic drugs—hypoglycaemic and anti-hyperglycaemic properties in mice.

<p>Vehicle, pioglitazone (30 mg/kg), gliclazide (8 mg/kg), metformin (200 mg/kg), sitagliptin (10 mg/kg), or 55P0110 (90 mg/kg) were orally administered to mice 45 min before a standard oral glucose tolerance test was started (3 g/kg). (<b>A</b>) Change in basal glycaemia 45 min after drug feeding („hypoglycaemic action“); (<b>B</b>) incremental area under the glucose curve (AUCinc; „anti-hyperglycaemic action“). Means±SEM; n = 8–27 each; *p<0.05; †p<0.01; ‡p<0.001 vs. 55P0110; §p<0.05 vs. vehicle.</p