Eleven amino acid glucagon-like peptide-1 receptor agonists with antidiabetic activity.
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.
Mapelli
Claudio
C
Department of Applied Biotechnologies, Bristol-Myers Squibb Company Research & Development, Pennington, New Jersey 08534, USA.
Natarajan
Sesha I
SI
Meyer
Jean-Philippe
JP
Bastos
Margarita M
MM
Bernatowicz
Michael S
MS
Lee
Ving G
VG
Pluscec
Jelka
J
Riexinger
Douglas J
DJ
Sieber-McMaster
Ellen S
ES
Constantine
Keith L
KL
Smith-Monroy
Constance A
CA
Golla
Rajasree
R
Ma
Zhengping
Z
Longhi
Daniel A
DA
Shi
Dan
D
Xin
Li
L
Taylor
Joseph R
JR
Koplowitz
Barry
B
Chi
Cecilia L
CL
Khanna
Ashish
A
Robinson
Gordon W
GW
Seethala
Ramakrishna
R
Antal-Zimanyi
Ildiko A
IA
Stoffel
Robert H
RH
Han
Songping
S
Whaley
Jean M
JM
Huang
Christine S
CS
Krupinski
John
J
Ewing
William R
WR
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*
C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D009842:Oligopeptides; D018027:Receptors, Glucagon