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Extensive Isomerization of Alkenes Using a Bifunctional Catalyst: An Alkene Zipper
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Extensive Isomerization of Alkenes Using a Bifunctional Catalyst: An Alkene Zipper
Novel exenatide analogs with peptidic albumin binding domains: potent anti-diabetic agents with extended duration of action.
The design, synthesis and pharmacology of novel long-acting exenatide analogs for the treatment of metabolic diseases are described. These molecules display enhanced pharmacokinetic profile and potent glucoregulatory and weight lowering actions compared to native exenatide. [Leu(14)]exenatide-ABD is an 88 residue peptide amide incorporating an Albumin Binding Domain (ABD) scaffold. [Leu(14)]exenatide-ABP is a 53 residue peptide incorporating a short Albumin Binding Peptide (ABP). [Leu(14)]exenatide-ABD and [Leu(14)]exenatide-ABP exhibited nanomolar functional GLP-1 receptor potency and were metabolically stable in vitro in human plasma and in a pancreatic digestive enzyme mixture. Both molecules displayed picomolar and nanomolar binding association with albumin across multiple species and circulating half lives of 16 and 11 hours, respectively, post a single IV dose in rats. Unlike exenatide, both molecules elicited robust glucose lowering when injected 1 day prior to an oral glucose tolerance test, indicative of their extended duration of action. [Leu(14)]exenatide-ABD was compared to exenatide in a Lep (ob/ob) mouse model of diabetes. Twice-weekly subcutaneously dosed [Leu(14)]exenatide-ABD displayed superior glucose lowering and weight loss in diabetic mice when compared to continuously infused exenatide at the same total weekly dose. A single oral administration of each molecule via an enteric coated capsule to cynomolgus monkeys showed superior pharmacokinetics for [Leu(14)]exenatide-ABD as compared to [Leu(14)]exenatide-ABP with detectable exposure longer than 14 days. These studies support the potential use of these novel long acting exenatide analogs with different routes of administration for the treatment of type 2 diabetes
PK profile of orally dosed peptides in monkeys.
<p>[Leu<sup>14</sup>]exenatide-ABD (▾) and [Leu<sup>14</sup>]exenatide-ABP (▿), n = 3. Data are presented as mean ± SEM.</p
Functional activity at the GLP-1 receptor.
<p>GLP-1 (7–36) (▪), [Leu<sup>14</sup>]exenatide-ABD (▾) and [Leu<sup>14</sup>]exenatide-ABP (▿). GLP-1 (7–36) was used as a reference standard in the assay. The assay was run in quadruplicates and data are presented as mean ± SD. Abbreviations: Fluorescence (F).</p
PK profile of intravenously dosed peptides in rats and monkeys.
<p>(A) rats, n = 3–4 and (B) monkeys, n = 3. Exenatide (▪), [Leu<sup>14</sup>]exenatide-ABD (▾) and [Leu<sup>14</sup>]exenatide-ABP (▿). Data are presented as mean ± SEM.</p
Four-week chronic dosing of peptides in diabetic <i>Lep<sup>ob/ob</sup></i> Mice.
<p>(A) effects on HbA1c (B) effects on body weight and (C) effects on food intake. Vehicle (□), [Leu<sup>14</sup>]exenatide-ABD (▾) and exenatide (▪). Data are presented as mean ± SEM, n = 10. *p<0.05 vs. vehicle, #p<0.05 vs. exenatide infusion by ANOVA with Tukey’s test.</p
<i>In Vitro</i> Activity, Metabolic Stability, and Plasma Glucose in OGTT.
<p>Stability results (measured as plasma AUC 0–5 h; pancreatin mix AUC 0–2 h)) are expressed as a percentage of peptide remaining versus stable control peptide ± SEM. Replicates within each assay n = 3, except for exenatide and [Leu<sup>14</sup>]exenatide-ABP where n = 2.</p
Binding Constants for Albumin Interactions at 25°C.
<p>The number in parentheses represents the standard deviation in the last significant digit.</p