Discovery of potent, orally active benzimidazole glucagon receptor antagonists.
The discovery and optimization of potent and selective aminobenzimidazole glucagon receptor antagonists are described. One compound possessing moderate pharmacokinetic properties in multiple preclinical species was orally efficacious at inhibiting glucagon-mediated glucose excursion in transgenic mice expressing the human glucagon receptor, and in rhesus monkeys. The compound also significantly lowered glucose levels in a murine model of diabetes.
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. ron_kim@merck.com
Ronald M
RM
Kim
Jiang
J
Chang
Ashley R
AR
Lins
Ed
E
Brady
Mari R
MR
Candelore
Qing
Q
Dallas-Yang
Victor
V
Ding
Jasminka
J
Dragovic
Susan
S
Iliff
Guoqiang
G
Jiang
Steven
S
Mock
Sajjad
S
Qureshi
Richard
R
Saperstein
Deborah
D
Szalkowski
Constantin
C
Tamvakopoulos
Laurie
L
Tota
Michael
M
Wright
Xiaodong
X
Yang
James R
JR
Tata
Kevin
K
Chapman
Bei B
BB
Zhang
Emma R
ER
Parmee
D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000493:pharmacokinetics; D016466:CHO Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods; D006224:Cricetinae; D003412:Cricetulus; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005934:Glucagon / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008253:Macaca mulatta; D051379:Mice; D008822:Mice, Transgenic; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D001562:Benzimidazoles; D018027:Receptors, Glucagon; D005934:Glucagon