title: Eleven amino acid glucagon-like peptide-1 receptor agonists with antidiabetic activity.
abstract: Glucagon-like peptide 1 (GLP-1) is a 30 or 31 amino acid peptide hormone that contributes to the physiological regulation of glucose homeostasis and food intake. Herein, we report the discovery of a novel class of 11 amino acid GLP-1 receptor agonists. These peptides consist of a structurally optimized 9-mer, which is closely related to the N-terminal 9 amino acids of GLP-1, linked to a substituted C-terminal biphenylalanine (BIP) dipeptide. SAR studies resulted in 11-mer GLP-1R agonists with similar in vitro potency to the native 30-mer. Peptides 21 and 22 acutely reduced plasma glucose excursions and increased plasma insulin concentrations in a mouse model of diabetes. These peptides also showed sustained exposures over several hours in mouse and dog models. The described 11-mer GLP-1 receptor agonists represent a new tool in further understanding GLP-1 receptor pharmacology that may lead to novel antidiabetic agents.
authors.affiliation: Department of Applied Biotechnologies, Bristol-Myers Squibb Company Research & Development, Pennington, New Jersey 08534, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Mapelli
authors.forename: Sesha I
authors.initials: SI
authors.lastname: Natarajan
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Meyer
authors.forename: Margarita M
authors.initials: MM
authors.lastname: Bastos
authors.forename: Michael S
authors.initials: MS
authors.lastname: Bernatowicz
authors.forename: Ving G
authors.initials: VG
authors.lastname: Lee
authors.forename: Jelka
authors.initials: J
authors.lastname: Pluscec
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Riexinger
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Sieber-McMaster
authors.forename: Keith L
authors.initials: KL
authors.lastname: Constantine
authors.forename: Constance A
authors.initials: CA
authors.lastname: Smith-Monroy
authors.forename: Rajasree
authors.initials: R
authors.lastname: Golla
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Ma
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Longhi
authors.forename: Dan
authors.initials: D
authors.lastname: Shi
authors.forename: Li
authors.initials: L
authors.lastname: Xin
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Taylor
authors.forename: Barry
authors.initials: B
authors.lastname: Koplowitz
authors.forename: Cecilia L
authors.initials: CL
authors.lastname: Chi
authors.forename: Ashish
authors.initials: A
authors.lastname: Khanna
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Robinson
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Seethala
authors.forename: Ildiko A
authors.initials: IA
authors.lastname: Antal-Zimanyi
authors.forename: Robert H
authors.initials: RH
authors.lastname: Stoffel
authors.forename: Songping
authors.initials: S
authors.lastname: Han
authors.forename: Jean M
authors.initials: JM
authors.lastname: Whaley
authors.forename: Christine S
authors.initials: CS
authors.lastname: Huang
authors.forename: John
authors.initials: J
authors.lastname: Krupinski
authors.forename: William R
authors.initials: WR
authors.lastname: Ewing
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011487:Protein Conformation; D018027:Receptors, Glucagon / Q000819:agonists*
chemical_list: C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D009842:Oligopeptides; D018027:Receptors, Glucagon