title: 4-arylcyclohexylalanine analogs as potent, selective, and orally active inhibitors of dipeptidyl peptidase IV.
abstract: A novel series of 4-arylcyclohexylalanine DPP-4 inhibitors was synthesized and tested for inhibitory activity as well as selectivity over the related proline-specific enzymes DPP-8 and DPP-9. Optimization of this series led to 28 (DPP-4 IC(50)=4.8 nM), which showed an excellent pharmacokinetic profile across several preclinical species. Evaluation of 28 in an oral glucose tolerance test demonstrated that this compound effectively reduced glucose excursion in lean mice.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. david_kaelin@merck.com
authors.forename: David E
authors.initials: DE
authors.lastname: Kaelin
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Smenton
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
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Duffy
mesh_terms: D000284:Administration, Oral; D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D054873:Dipeptidyl-Peptidase IV Inhibitors; D051379:Mice; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011480:Protease Inhibitors; D000409:Alanine