Small molecule ago-allosteric modulators of the human glucagon-like peptide-1 (hGLP-1) receptor.
Following our previous publication describing the biological profiles, we herein describe the structure-activity relationships of a core set of quinoxalines as the hGLP-1 receptor agonists. The most potent and efficacious compounds are 6,7-dichloroquinoxalines bearing an alkyl sulfonyl group at the C-2 position and a secondary alkyl amino group at the C-3 position. These findings serve as a valuable starting point for the discovery of more drug-like small molecule agonists for the hGLP-1 receptor.
Teng
Min
M
Department of Medicinal Chemistry, Pfizer Global Research and Development, La Jolla, 10770 Science Center Dr., San Diego, CA 92121-1194, USA. min.teng@pfizer.com
Johnson
Michael D
MD
Thomas
Christine
C
Kiel
Dan
D
Lakis
James N
JN
Kercher
Tim
T
Aytes
Shelley
S
Kostrowicki
Jarek
J
Bhumralkar
Dilip
D
Truesdale
Larry
L
May
John
J
Sidelman
Ulla
U
Kodra
Janos T
JT
Jørgensen
Anker Steen
AS
Olesen
Preben Houlberg
PH
de Jong
Johannes Cornelis
JC
Madsen
Peter
P
Behrens
Carsten
C
Pettersson
Ingrid
I
Knudsen
Lotte Bjerre
LB
Holst
Jens J
JJ
Lau
Jesper
J
D000242:Cyclic AMP / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007202:Indicators and Reagents; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000819:agonists*; D013329:Structure-Activity Relationship