title: Structure-activity-relationship of amide and sulfonamide analogs of omarigliptin.
abstract: A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed phase III clinical development and has been approved in Japan.
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Dennis
authors.initials: D
authors.lastname: Feng
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Qian
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: James
authors.initials: J
authors.lastname: Apgar
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Wilkening
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Kuethe
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Ying-Duo
authors.initials: YD
authors.lastname: Gao
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Scapin
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Cox
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: George
authors.initials: G
authors.lastname: Doss
authors.affiliation: Department of Pharmacology, Screening & Protein Sciences, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: George
authors.initials: G
authors.lastname: Eiermann
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Huaibing
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Lyons
authors.affiliation: Department of Cardiometabolic Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Metzger
authors.affiliation: Department of Pharmacology, Screening & Protein Sciences, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Petrov
authors.affiliation: Department of Cardiometabolic Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Wu
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Shiyao
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Weber
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Cardiometabolic Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Ranabir Sinha
authors.initials: RS
authors.lastname: Roy
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Tesfaye
authors.initials: T
authors.lastname: Biftu
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004285:Dogs; D006207:Half-Life; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: C587539:2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo(3,4-c)pyrazol-5(4H)-yl)tetrahydro-2H-pyran-3-amine; D000577:Amides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D011714:Pyrans; D013449:Sulfonamides; D018819:Dipeptidyl Peptidase 4
keywords: DPP-4 inhibitor; DPP-8; DPP-9; Omarigliptin; Pyrazolopyrolidine; Sitagliptin; Type 2 diabetes; X-ray