Identification of potent 11mer glucagon-like peptide-1 receptor agonist peptides with novel C-terminal amino acids: Homohomophenylalanine analogs.
We report the identification of potent agonists of the Glucagon-Like Peptide-1 Receptor (GLP-1R). These compounds are short, 11 amino acid peptides containing several unnatural amino acids, including (in particular) analogs of homohomophenylalanine (hhPhe) at the C-terminal position. Typically the functional activity of the more potent peptides in this class is in the low picomolar range in an in vitro cAMP assay, with one example demonstrating excellent in vivo activity in an ob/ob mouse model of diabetes.
Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA. tasir.haque@bms.com
Tasir S
TS
Haque
Ving G
VG
Lee
Douglas
D
Riexinger
Ming
M
Lei
Sarah
S
Malmstrom
Li
L
Xin
Songping
S
Han
Claudio
C
Mapelli
Christopher B
CB
Cooper
Ge
G
Zhang
William R
WR
Ewing
John
J
Krupinski
D000595:Amino Acid Sequence; D000613:Aminobutyrates / Q000737:chemistry*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000067757:Glucagon-Like Peptide-1 Receptor; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018027:Receptors, Glucagon / Q000819:agonists*
D000613:Aminobutyrates; D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; C014328:2-amino-4-phenylbutyric acid