title: Boc5, a non-peptidic glucagon-like Peptide-1 receptor agonist, invokes sustained glycemic control and weight loss in diabetic mice.
abstract: 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.
authors.affiliation: The National Center for Drug Screening, Shanghai, China.
authors.forename: Haoran
authors.initials: H
authors.lastname: Su
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.forename: Jia
authors.initials: J
authors.lastname: Wang
authors.forename: Yiqian
authors.initials: Y
authors.lastname: Wang
authors.forename: Weiwei
authors.initials: W
authors.lastname: Gao
authors.forename: Ling
authors.initials: L
authors.lastname: Zhou
authors.forename: Jiayu
authors.initials: J
authors.lastname: Liao
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Young
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Wang
mesh_terms: 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
chemical_list: D001786:Blood Glucose; D003503:Cyclobutanes; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin; D018027:Receptors, Glucagon; C533559:Boc5 compound; C000593834:Glp1r protein, mouse