Optimization of 1,4-diazepan-2-one containing dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes.
Following the discovery of N-acyl-1,4-diazepan-2-one as a novel pharmacophore for potent and selective DPP-4 inhibitors, optimization of this new lead with different substitution on the seven-membered ring resulted in several highly potent and selective, orally bioavailable, and efficacious DPP-4 inhibitors, such as 3R-methyl-1-cyclopropyl-1,4-diazepan-2-one derivative 9i (DPP-4 IC(50)=8.0 nM) and 3R,6R-dimethyl-1,4-diazepan-2-one derivative 14a (DPP-4 IC(50)=9.7 nM).
Liang
Gui-Bai
GB
Merck Research Laboratories, Department of Medicinal Chemistry, Merck and Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. gui-bai_liang@merck.com
Qian
Xiaoxia
X
Feng
Dennis
D
Biftu
Tesfaye
T
Eiermann
George
G
He
Huaibing
H
Leiting
Barbara
B
Lyons
Kathy
K
Petrov
Aleksandr
A
Sinha-Roy
Ranabir
R
Zhang
Bei
B
Wu
Joseph
J
Zhang
Xiaoping
X
Thornberry
Nancy A
NA
Weber
Ann E
AE
D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008956:Models, Chemical; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley
C521289:1,4-diazepan-2-one; D001381:Azepines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors