title: 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.
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Brunmair
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Lehner
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Stadlbauer
authors.affiliation: 55pharma Drug Discovery & Development AG, Vienna, Austria.
authors.forename: Immanuel
authors.initials: I
authors.lastname: Adorjan
authors.affiliation: 55pharma Drug Discovery & Development AG, Vienna, Austria.
authors.forename: Klaus
authors.initials: K
authors.lastname: Frobel
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Scherer
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Anton
authors.initials: A
authors.lastname: Luger
authors.affiliation: 55pharma Drug Discovery & Development AG, Vienna, Austria.
authors.forename: Leonhardt
authors.initials: L
authors.lastname: Bauer
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Clemens
authors.initials: C
authors.lastname: Fürnsinn
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D011807:Quinolizines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D012372:ROC Curve
chemical_list: C000605111:55P0110; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D011807:Quinolizines; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse