Design and synthesis of conformationally constrained tri-substituted ureas as potent antagonists of the human glucagon receptor.
A series of conformationally constrained tri-substituted ureas were synthesized, and their potential as glucagon receptor antagonists was evaluated. This effort resulted in the identification of compound 4a, which had a binding IC50 of 4.0 nM and was shown to reduce blood glucose levels at 3 mg/kg in glucagon-challenged mice containing a humanized glucagon receptor. Compound 4a was efficacious in correcting hyperglycemia induced by a high fat diet in transgenic mice at an oral dose as low as 3 mg/kg.
Liang
Rui
R
Department of Basic Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. rui_liang@merck.com
Abrardo
Lauren
L
Brady
Edward J
EJ
Candelore
Mari Rios
MR
Ding
Victor
V
Saperstein
Richard
R
Tota
Laurie M
LM
Wright
Michael
M
Mock
Steve
S
Tamvakopolous
Constantin
C
Tong
Sharon
S
Zheng
Song
S
Zhang
Bei B
BB
Tata
James R
JR
Parmee
Emma R
ER
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004041:Dietary Fats; D015195:Drug Design; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D005934:Glucagon / Q000037:antagonists & inhibitors; D006207:Half-Life; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced / Q000517:prevention & control; D007202:Indicators and Reagents; D051379:Mice; D008822:Mice, Transgenic; D008968:Molecular Conformation; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000235:genetics; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
D001786:Blood Glucose; D004041:Dietary Fats; D007202:Indicators and Reagents; D018027:Receptors, Glucagon; D005749:Gastric Inhibitory Polypeptide; D014508:Urea; D005934:Glucagon; D000242:Cyclic AMP