title: Optimization of 1,4-diazepan-2-one containing dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes.
abstract: 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).
authors.affiliation: Merck Research Laboratories, Department of Medicinal Chemistry, Merck and Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. gui-bai_liang@merck.com
authors.forename: Gui-Bai
authors.initials: GB
authors.lastname: Liang
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Qian
authors.forename: Dennis
authors.initials: D
authors.lastname: Feng
authors.forename: Tesfaye
authors.initials: T
authors.lastname: Biftu
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: 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: 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
chemical_list: C521289:1,4-diazepan-2-one; D001381:Azepines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors