Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor.
A novel class of antagonists of the human glucagon receptor (hGCGR) has been discovered. Systematic modification of the lead compound identified substituents that were essential for activity and those that were amenable to further optimization. This SAR exploration resulted in the synthesis of 13, which exhibited good potency as an hGCGR functional antagonist (IC50 = 34 nM) and moderate bioavailability (36% in mice).
Duffy
Joseph L
JL
Department of Basic Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. joseph_duffy@merck.com
Kirk
Brian A
BA
Konteatis
Zenon
Z
Campbell
Elizabeth L
EL
Liang
Rui
R
Brady
Edward J
EJ
Candelore
Mari Rios
MR
Ding
Victor D H
VD
Jiang
Guoqiang
G
Liu
Frank
F
Qureshi
Sajjad A
SA
Saperstein
Richard
R
Szalkowski
Deborah
D
Tong
Sharon
S
Tota
Lauri M
LM
Xie
Dan
D
Yang
Xiaodong
X
Zafian
Peter
P
Zheng
Song
S
Chapman
Kevin T
KT
Zhang
Bei B
BB
Tata
James R
JR
D006801:Humans; D015394:Molecular Structure; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000145:classification / Q000494:pharmacology*
D018027:Receptors, Glucagon; D013876:Thiophenes