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.
Kim
Ronald M
RM
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. ron_kim@merck.com
Chang
Jiang
J
Lins
Ashley R
AR
Brady
Ed
E
Candelore
Mari R
MR
Dallas-Yang
Qing
Q
Ding
Victor
V
Dragovic
Jasminka
J
Iliff
Susan
S
Jiang
Guoqiang
G
Mock
Steven
S
Qureshi
Sajjad
S
Saperstein
Richard
R
Szalkowski
Deborah
D
Tamvakopoulos
Constantin
C
Tota
Laurie
L
Wright
Michael
M
Yang
Xiaodong
X
Tata
James R
JR
Chapman
Kevin
K
Zhang
Bei B
BB
Parmee
Emma R
ER
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