Discovery of N-aryl-2-acylindole human glucagon receptor antagonists.
A novel class of N-aryl-2-acylindole human glucagon receptor (hGCGR) antagonists is reported. These compounds demonstrate good pharmacokinetic profiles in multiple preclinical species. One compound from this series, indole 33, is orally active in a transgenic murine pharmacodynamic model. Furthermore, a 1mg/kg oral dose of indole 33 lowers ambient glucose levels in an ob/ob/hGCGR transgenic murine diabetes model. This compound was deemed suitable for preclinical safety studies and was found to be well tolerated in an 8-day experimental rodent tolerability study. The combination of preclinical efficacy and safety observed with compound 33 highlights the potential of this class as a treatment for type 2 diabetes.
Discovery and Preclinical Sciences, Merck Research Laboratories, Rahway, NJ 07065, USA. christopher_sinz@merck.com
Christopher
C
Sinz
Amy
A
Bittner
Ed
E
Brady
Mari
M
Candelore
Qing
Q
Dallas-Yang
Victor
V
Ding
Guoqiang
G
Jiang
Zhen
Z
Lin
Sajjad
S
Qureshi
Gino
G
Salituro
Richard
R
Saperstein
Jackie
J
Shang
Deborah
D
Szalkowski
Laurie
L
Tota
Stella
S
Vincent
Michael
M
Wright
Shiyao
S
Xu
Xiaodong
X
Yang
Bei
B
Zhang
James
J
Tata
Ronald
R
Kim
Emma R
ER
Parmee
D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007211:Indoles; D018027:Receptors, Glucagon