Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119.
GPR119 is a rhodopsin-like GPCR expressed in pancreatic beta-cells and incretin releasing cells in the GI tract. As with incretins, GPR119 increases cAMP levels in these cell types, thus making it a highly attractive potential target for the treatment of diabetes. The discovery of the first reported potent agonist of GPR119, 2-fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine (8g, AR231453), is described starting from an initial inverse agonist screening hit. Compound 8g showed in vivo activity in rodents and was active in an oral glucose tolerance test in mice following oral administration.
Semple
Graeme
G
Department of Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121, USA. gsemple@arenapharm.com
Fioravanti
Beatriz
B
Pereira
Guillherme
G
Calderon
Imelda
I
Uy
Jane
J
Choi
Karoline
K
Xiong
Yifeng
Y
Ren
Albert
A
Morgan
Michael
M
Dave
Vibha
V
Thomsen
William
W
Unett
David J
DJ
Xing
Charles
C
Bossie
Stuart
S
Carroll
Chris
C
Chu
Zhi-Liang
ZL
Grottick
Andrew J
AJ
Hauser
Erin K
EK
Leonard
James
J
Jones
Robert M
RM
D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
D001786:Blood Glucose; C532423:GPR119 protein, rat; C516207:Gpr119 protein, mouse; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled