Integration of optimized substituent patterns to produce highly potent 4-aryl-pyridine glucagon receptor antagonists.
Optimized substituent patterns in 4-aryl-pyridine glucagon receptor antagonists were merged to produce highly potent derivatives containing both a 3-[(1R)-hydroxyethyl] and a 2'-hydroxy group. Due to restricted rotation of the phenyl-pyridine bond, these analogues exist as four isomers. A diastereoselective methylcopper reaction was developed to facilitate the synthesis, and single isomers were isolated with activities in the range IC(50)=10-25 nM.
Ladouceur
Gaetan H
GH
Department of Chemistry Research, Bayer Research Center, West Haven, CT 06516, USA. gaetan.ladouceur.b@bayer.com
Cook
James H
JH
Hertzog
Donald L
DL
Jones
J Howard
JH
Hundertmark
Thomas
T
Korpusik
Mary
M
Lease
Timothy G
TG
Livingston
James N
JN
MacDougall
Margit L
ML
Osterhout
Martin H
MH
Phelan
Kathleen
K
Romero
Romulo H
RH
Schoen
William R
WR
Shao
Chunning
C
Smith
Roger A
RA
D001593:Benzyl Compounds / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001593:Benzyl Compounds; D011725:Pyridines; D018027:Receptors, Glucagon