title: (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.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. Tesfaye_Biftu@merck.com
authors.forename: Tesfaye
authors.initials: T
authors.lastname: Biftu
authors.forename: Dennis
authors.initials: D
authors.lastname: Feng
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Qian
authors.forename: Gui-Bai
authors.initials: GB
authors.lastname: Liang
authors.forename: Gerard
authors.initials: G
authors.lastname: Kieczykowski
authors.forename: George
authors.initials: G
authors.lastname: Eiermann
authors.forename: Huaibing
authors.initials: H
authors.lastname: He
authors.forename: Barbara
authors.initials: B
authors.lastname: Leiting
authors.forename: Kathy
authors.initials: K
authors.lastname: Lyons
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Petrov
authors.forename: Ranabir
authors.initials: R
authors.lastname: Sinha-Roy
authors.forename: Bei
authors.initials: B
authors.lastname: Zhang
authors.forename: Giovanna
authors.initials: G
authors.lastname: Scapin
authors.forename: Sangita
authors.initials: S
authors.lastname: Patel
authors.forename: Ying-Duo
authors.initials: YD
authors.lastname: Gao
authors.forename: Suresh
authors.initials: S
authors.lastname: Singh
authors.forename: Joseph
authors.initials: J
authors.lastname: Wu
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Thornberry
authors.forename: Ann E
authors.initials: AE
authors.lastname: Weber
mesh_terms: 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
chemical_list: 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