Boc5, a non-peptidic glucagon-like Peptide-1 receptor agonist, invokes sustained glycemic control and weight loss in diabetic mice.
BACKGROUND
Our recent discovery of the substituted cyclobutane Boc5, one of the first non-peptidic agonists at glucagon-like peptide-1 receptors, offers the potential of combining oral availability with full agonism capable of eliciting antidiabetic and antiobesity effects. The present study was aimed at determining the in vivo pharmacologic properties of Boc5 in both normal and diabetic mice following chronic administration, with emphasis on glycemic control and weight loss.


RESULTS
C57BL/6J and db/db mice were treated daily with Boc5 for 4 weeks and a range of pharmacologic parameters, including hemoglobin A1c, intraperitoneal glucose tolerance, insulin tolerance, fasting insulin and leptin levels, food intake, body weight and fat mass, were assessed before and after the treatment. Effects on food intake, gastric emptying, and insulinogenic index were also investigated in animals acutely administered with Boc5. Boc5 (3 mg) was able to induce a durable restoration of glycemic control (normalization of both hemoglobin A1c and intraperitoneal glucose tolerance) in db/db mice, following 4 weeks of daily administration. As with peptidic glucagon-like peptide-1 receptor agonists, its glycemic benefit and weight (fat) loss were associated with dose-dependent effects that included reduction in food intake, slowing of gastric emptying (both of which reduce nutrient-drive at beta-cells), stimulation of insulin secretion (which was glucose-dependent), and elevation in insulin sensitivity. There was little effect on normal mice treated in the same manner.


CONCLUSIONS
Our findings suggest that Boc5 is the only non-peptidic molecule reported thus far to simultaneously activate this spectrum of antidiabetic effects.
Su
Haoran
H
The National Center for Drug Screening, Shanghai, China.
He
Min
M
Li
Hongmei
H
Liu
Qing
Q
Wang
Jia
J
Wang
Yiqian
Y
Gao
Weiwei
W
Zhou
Ling
L
Liao
Jiayu
J
Young
Andrew A
AA
Wang
Ming-Wei
MW
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003503:Cyclobutanes / Q000494:pharmacology*; D003920:Diabetes Mellitus / Q000097:blood*; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018027:Receptors, Glucagon / Q000819:agonists*; D012016:Reference Values; D015431:Weight Loss
D001786:Blood Glucose; D003503:Cyclobutanes; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin; D018027:Receptors, Glucagon; C533559:Boc5 compound; C000593834:Glp1r protein, mouse