Substituted imidazoles as glucagon receptor antagonists.
A modestly active, nonselective triarylimidazole lead was optimized for binding affinity with the human glucagon receptor. This led to the identification of a 2- and/or 4-alkyl or alkyloxy substituent on the imidazole C4-aryl group as a structural determinant for significant enhancement in binding with the glucagon receptor (e.g., 41, IC(50)=0.053 microM) and selectivity (>1000x) over p38MAP kinase in this class of compounds.
Chang
L L
LL
Department of Medicinal Chemical Research, Merck Research Laboratories, Rahway, NJ 07065, USA. linda_chang@merck.com
Sidler
K L
KL
Cascieri
M A
MA
de Laszlo
S
S
Koch
G
G
Li
B
B
MacCoss
M
M
Mantlo
N
N
O'Keefe
S
S
Pang
M
M
Rolando
A
A
Hagmann
W K
WK
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008274:Magnesium / Q000378:metabolism / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases
D007093:Imidazoles; D011725:Pyridines; D018027:Receptors, Glucagon; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D008274:Magnesium