(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.
Replacement of the triazolopiperazine ring of sitagliptin (DPP-4 IC(50)=18nM) with 3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one gave dipeptidyl peptidase IV (DPP-4) inhibitor 1 which is potent (DPP-4 IC(50)=2.6nM), selective, and efficacious in an oral glucose tolerance test in mice. It was selected for extensive preclinical development as a potential back-up candidate to sitagliptin.
Biftu
Tesfaye
T
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. Tesfaye_Biftu@merck.com
Feng
Dennis
D
Qian
Xiaoxia
X
Liang
Gui-Bai
GB
Kieczykowski
Gerard
G
Eiermann
George
G
He
Huaibing
H
Leiting
Barbara
B
Lyons
Kathy
K
Petrov
Aleksandr
A
Sinha-Roy
Ranabir
R
Zhang
Bei
B
Scapin
Giovanna
G
Patel
Sangita
S
Gao
Ying-Duo
YD
Singh
Suresh
S
Wu
Joseph
J
Zhang
Xiaoping
X
Thornberry
Nancy A
NA
Weber
Ann E
AE
D000818:Animals; D001381:Azepines / Q000737:chemistry* / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D011487:Protein Conformation; D011719:Pyrazines / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000737:chemistry / Q000627:therapeutic use
C518995:4-(3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one; D001381:Azepines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011480:Protease Inhibitors; D011719:Pyrazines; D014230:Triazoles; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate