Exploration of structure-activity relationships at the two C-terminal residues of potent 11mer Glucagon-Like Peptide-1 receptor agonist peptides via parallel synthesis.
We report the identification of potent agonists of the Glucagon-Like Peptide-1 receptor (GLP-1R) via evaluation of two positional scanning libraries and a two-dimensional focused library, synthesized in part on SynPhase Lanterns. These compounds are 11 amino acid peptides containing several unnatural amino acids, including (in particular) analogs of biphenylalanine (Bip) at the two C-terminal positions. Typical activities of the most potent peptides in this class are in the picomolar range in an in vitro functional assay using human GLP-1 receptor.
Haque
Tasir S
TS
Department of Discovery Chemistry, Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
Martinez
Rogelio L
RL
Lee
Ving G
VG
Riexinger
Douglas G
DG
Lei
Ming
M
Feng
Ming
M
Koplowitz
Barry
B
Mapelli
Claudio
C
Cooper
Christopher B
CB
Zhang
Ge
G
Huang
Christine
C
Ewing
William R
WR
Krupinski
John
J
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000819:agonists*; D013329:Structure-Activity Relationship
C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D019151:Peptide Library; D010455:Peptides; D018027:Receptors, Glucagon