Optimization of the 4-aryl group of 4-aryl-pyridine glucagon antagonists: development of an efficient, alternative synthesis.
A narrow structure-activity relationship was established for the 4-aryl group in 4-aryl-pyridine glucagon antagonists, with only small substituents being well-tolerated, and only at the 3'- and 4'-positions. However, substitution with a 2'-hydroxy group gave a ca. 3-fold increase in activity (e.g., 4'-fluoro-2'-hydroxy analogue 33, IC50=190 nM). For efficient preparation of 2'-substituted phenylpyridines, a novel synthesis via pyrones and 4-methoxy-pyridines was developed.
Smith
Roger A
RA
Department of Chemistry Research, Bayer Research Center, 400Morgan Lane, West Haven, CT 06516, USA. roger.smith.b@bayer.com
Hertzog
Donald L
DL
Osterhout
Martin H
MH
Ladouceur
Gaetan H
GH
Korpusik
Mary
M
Bobko
Mark A
MA
Jones
J Howard
JH
Phelan
Kathleen
K
Romero
Romulo H
RH
Hundertmark
Thomas
T
MacDougall
Margit L
ML
Livingston
James N
JN
Schoen
William R
WR
D005934:Glucagon / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D011725:Pyridines; D005934:Glucagon; C023666:pyridine