Discovery of novel, potent, and orally active spiro-urea human glucagon receptor antagonists.
A novel class of spiro-ureas has been discovered as potent human glucagon receptor antagonists in both binding and functional assays. Preliminary studies have revealed that compound 15 is an orally active human glucagon receptor antagonist in a transgenic murine pharmacodynamic model at 10 and 30 mpk. Compound 15 is orally bioavailable in several preclinical species and shows selectivity toward cardiac ion channels and other family B receptors, such as hGIP1 and hGLP.
Shen
Dong-Ming
DM
Department of Basic Chemistry, Merck Research Laboratories, PO Box 2000, RY50G-146, Rahway, NJ 07065, USA. dongming_shen@merck.com
Zhang
Fengqi
F
Brady
Edward J
EJ
Candelore
Mari Rios
MR
Dallas-Yang
Qing
Q
Ding
Victor D-H
VD
Dragovic
Jasminka
J
Feeney
William P
WP
Jiang
Guoquiang
G
McCann
Peggy E
PE
Mock
Steve
S
Qureshi
Sajjad A
SA
Saperstein
Richard
R
Shen
Xiaolan
X
Tamvakopoulos
Constantin
C
Tong
Xinchun
X
Tota
Laurie M
LM
Wright
Michael J
MJ
Yang
Xiaodong
X
Zheng
Song
S
Chapman
Kevin T
KT
Zhang
Bei B
BB
Tata
James R
JR
Parmee
Emma R
ER
D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D014508:Urea / Q000737:chemistry / Q000494:pharmacology*
D018027:Receptors, Glucagon; D013141:Spiro Compounds; D014508:Urea