title: Novel exenatide analogs with peptidic albumin binding domains: potent anti-diabetic agents with extended duration of action.
abstract: 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.
authors: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
authors: Odile E
authors: OE
authors: Levy
authors: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
authors: Carolyn M
authors: CM
authors: Jodka
authors: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
authors: Shijun Steven
authors: SS
authors: Ren
authors: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
authors: Lala
authors: L
authors: Mamedova
authors: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
authors: Abhinandini
authors: A
authors: Sharma
authors: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
authors: Manoj
authors: M
authors: Samant
authors: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
authors: Lawrence J
authors: LJ
authors: D'Souza
authors: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
authors: Christopher J
authors: CJ
authors: Soares
authors: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
authors: Diane R
authors: DR
authors: Yuskin
authors: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
authors: Li Jenny
authors: LJ
authors: Jin
authors: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
authors: David G
authors: DG
authors: Parkes
authors: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
authors: Krystyna
authors: K
authors: Tatarkiewicz
authors: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
authors: Soumitra S
authors: SS
authors: Ghosh
mesh_terms: D000284:Administration, Oral; D000418:Albumins / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D003921:Diabetes Mellitus, Experimental; D004195:Disease Models, Animal; D004355:Drug Stability; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D007700:Kinetics; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D051381:Rats; D018027:Receptors, Glucagon / Q000378:metabolism; D014688:Venoms / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D000418:Albumins; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide