Boc5, a Non-Peptidic Glucagon-Like Peptide-1 Receptor Agonist, Invokes Sustained Glycemic Control and Weight Loss in Diabetic Mice

Abstract

BackgroundOur 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.Methodology/Principal FindingsC57BL/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 β-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/SignificanceOur findings suggest that Boc5 is the only non-peptidic molecule reported thus far to simultaneously activate this spectrum of antidiabetic effects.

The role of serum albumin in the metabolism of Boc5: Molecular identification, species differences and contribution to plasma metabolism

“…was much shorter than its in SD rat (Chen et al, 2007), as well as why TCA cannot be detected in plasma and serum albumin from human, pig and rat. Although it has been well accepted that the glucose responsiveness of rodents and human islets are similar and mouse is always selected to set the T2DM model for in vivo pharmacological assessment (Sloop et al, 2010;Su et al 2008), our findings suggest that mouse is not ideal model for in vivo pharmacological assessment of Boc5, due to the significant species differences in Boc5 metabolism between mouse and human. From the both pharmacological assessment and drug metabolism views, rat is more suitable for serving as a surrogate model in whole tests of Boc5, such as pharmacokinetics studies, as well as the toxicological and pharmacological researches.…”

“…1), the first nonpeptidic agonist for GLP-1R, was discovered in 2007 following a high-throughput screening campaign against 48,160 small molecular compounds, by using luciferase reporter assay in HEK293 cells which stably expressed the rat GLP-1R gene linked to cAMP response element (Chen et al, 2007). Boc5 was recognized as a promising lead compound for T2DM and obesity treatment, due to this novel compound was found with the ability to invoke sustained glycemic control and weight loss in both genetic model (db/db mice) and diet-induced obese mice but not in normal animals (Chen et al, 2007;Su et al, 2008;He et al, 2010).…”

Non-peptidic glucose-like peptide-1 receptor agonists: aftermath of a serendipitous discovery

“…The remaining eight molecules possess fairly diverse structural features. Despite what were described by the inventors for these compounds in terms of orthosteric, allosteric, ago-allosteric, inverse, or partial/full agonists, their functional varieties are manifested in the following manners: (1) inducing both biochemical and cellular responses without in vivo activities [24,27] ; (2) behaving like an antagonist in cell-based assays (eg, T0632) [27] ; (3) promoting native ligand binding to the receptor in vitro [32] ; (4) demonstrating a full range of GLP-1 properties including in vivo efficacy [25,26] ; and (5) enhancing GLP-1 activities via binding to the receptor [33] . Since no distinct commonality could be found in the structures of these five types of compounds, their binding to the GLP-1 receptor must be realized via different sites.…”

“…Since no distinct commonality could be found in the structures of these five types of compounds, their binding to the GLP-1 receptor must be realized via different sites. Among them, Boc5 is the only one that demonstrated therapeutic benefits in vivo [25,26] . While peptidic GLP-1 mimetics displayed some side effects such as nausea and vomiting in the clinic [9] , both normal and diabetic db/db mice are highly tolerable to Boc5 [25] such that a similar reaction on the conditioned taste aversion required a dose well beyond the therapeutic window [26] .…”

“…These are the questions that must be addressed in order to sustain the vitality of a research program in this particular area. [24] K i : 1.47 µmol/L EC 50 : 2.73 µmol/L Diabetic db/db mice: Caused the release of reduction in food intake, insulin from normal rat body weight, gastric islets [22] emptying, blood glucose, HbA1c, insulin resistance, etc [25,26] Boc5, full agonist [25] K i : 287 nmol/L EC 50 : 1.08 µmol/L Diabetic db/db mice: At concentrations up to HbA1c was robustly 10 µmol/L evoked lowered [25] maximally only 37% of the GLP-1 response S4P, partial agonist [25] IC 50 : 0.62 µmol/L Decreased the basal GLP-1R Not reported (wild type receptor) activity during a short incuba-(C347-QQRY mutant tion while increased the receptor) surface distribution of the C347-QQRY GLP-1R mutant after a long incubation; rightshifted the dose-response T0632, inverse agonist [27] curve of GLP-1 [28] IC 50 [29] Enhanced GLP-1 binding EC 50 : 0.16 µmol/L Not reported EC 50 : 0.032 µmol/L) [32] E max (%): 85% Caused the release of insulin from normal mouse islets and a perfused rat pancreas [32] Ago-allosteric modulator [30][31][32] …”