title: Design, synthesis, structure-activity relationships, and docking studies of 1-(γ-1,2,3-triazol substituted prolyl)-(S)-3,3-difluoropyrrolidines as a novel series of potent and selective dipeptidyl peptidase-4 inhibitors.
abstract: Dipeptidyl peptidase-4 inhibitors hold great potential for the treatment of type 2 diabetes. A series of 1-(γ-1,2,3-triazol substituted prolyl)-(S)-3,3-difluoropyrrolidines were designed, synthesized, and evaluated as novel dipeptidyl peptidase-4 inhibitors. Most of the compounds exhibited good in vitro potency against dipeptidyl peptidase-4. Among these, compounds 7j, 7q, and 7s displayed good dipeptidyl peptidase-4 activity and excellent selectivity versus other proteases including dipeptidyl peptidase-8, dipeptidyl peptidase-9, and FAP. The possible binding modes of compounds 7j, 7q, and 7s with dipeptidyl peptidase-4 were also explored by molecular docking simulation.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Mingbo
authors.initials: M
authors.lastname: Su
authors.forename: Jingya
authors.initials: J
authors.lastname: Li
authors.forename: Xun
authors.initials: X
authors.lastname: Ji
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.forename: Zeng
authors.initials: Z
authors.lastname: Li
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
mesh_terms: D001665:Binding Sites; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
chemical_list: C586330:1-(5-((3,3-difluoropyrrolidin-1-yl)carbonyl)pyrrolidin-3-yl)-4-(4-fluoro-3-methylphenyl)-1H-1,2,3-triazole; C586332:1-(5-((3,3-difluoropyrrolidin-1-yl)carbonyl)pyrrolidin-3-yl)-4-(4-phenylphenyl)-1H-1,2,3-triazole; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D014230:Triazoles; C586331:methyl 1-(5-((3,3-difluoropyrrolidin-1-yl)carbonyl)pyrrolidin-3-yl)-1H-1,2,3-triazole-4-carboxylate; D011392:Proline; D018819:Dipeptidyl Peptidase 4