title: Synthesis and structure-activity relationships of potent 1-(2-substituted-aminoacetyl)-4-fluoro-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors.
abstract: Dipeptidyl peptidase IV (DPP-IV) inhibitors have attracted attention as potential drugs for use in the treatment of type 2 diabetes because they prevent the degradation of glucagon-like peptide-1 (GLP-1) and extend its duration of action. We previously reported that 2-cyano-4-fluoropyrrolidines act as potent DPP-IV inhibitors and have been modifying the 1-position of pyrrolidine to obtain more useful inhibitors. An L-tert-butylglycine derivative was found to be a stable and potent DPP-IV inhibitor that exhibits a glucose lowering effect in vivo. Here, we report the synthesis of and biological data on the aforementioned derivatives.
authors.affiliation: Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, Saitama, Japan. hiroshi.fukushima@po.rd.taisho.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukushima
authors.forename: Akira
authors.initials: A
authors.lastname: Hiratate
authors.forename: Masato
authors.initials: M
authors.lastname: Takahashi
authors.forename: Masako
authors.initials: M
authors.lastname: Saito-Hori
authors.forename: Eiji
authors.initials: E
authors.lastname: Munetomo
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Kitano
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Saito
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takaoka
authors.forename: Koji
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D011392:Proline / Q000737:chemistry; D013329:Structure-Activity Relationship; D014633:Valine / Q000737:chemistry / Q000494:pharmacology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D011392:Proline; D014633:Valine