title: 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives as potent, selective, and orally bioavailable inhibitors of dipeptidyl peptidase IV.
abstract: A novel series of 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives were designed and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4). The phenylalanine series afforded compounds such as 10 that were potent and selective (DPP-4, IC(50)=28nM), but exhibited limited oral bioavailability. The corresponding cyclohexylalanine derivatives such as 25 afforded improved PK exposure and efficacy in a murine OGTT experiment. The X-ray crystal structure of 25 bound to the DPP-4 active site is presented.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. joseph_duffy@merck.com
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Duffy
authors.forename: Brian A
authors.initials: BA
authors.lastname: Kirk
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: George J
authors.initials: GJ
authors.lastname: Eiermann
authors.forename: Huaibing
authors.initials: H
authors.lastname: He
authors.forename: Barbara
authors.initials: B
authors.lastname: Leiting
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Lyons
authors.forename: Reshma A
authors.initials: RA
authors.lastname: Patel
authors.forename: Sangita B
authors.initials: SB
authors.lastname: Patel
authors.forename: Alexsandr
authors.initials: A
authors.lastname: Petrov
authors.forename: Giovanna
authors.initials: G
authors.lastname: Scapin
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Wu
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; D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000737:chemistry / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C521364:4-aminocyclohexylalanine; D003510:Cyclohexanes; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; C009722:4-aminophenylalanine; D010649:Phenylalanine; D018819:Dipeptidyl Peptidase 4; D000409:Alanine