title: Synthesis and structure-activity relationships of potent 4-fluoro-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors.
abstract: Dipeptidyl peptidase IV (DPP-IV) inhibitors are promising antidiabetic drugs, and several drugs are in the developmental stage. We previously reported that the introduction of fluorine to the 4-position of 2-cyanopyrrolidine enhanced the DPP-IV inhibitory effect. In the present report, we examined the structure-activity relationship (SAR) of 2-cyano-4-fluoropyrrolidine with N-substituted glycine at the 1-position. We report the identification of a potent and stable DPP-IV inhibitor (TS-021) with a long-term persistent plasma drug concentration and a potent antihyperglycemic activity.
authors.affiliation: Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403, Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, 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: Ayako
authors.initials: A
authors.lastname: Mikami
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: Sumi
authors.initials: S
authors.lastname: Chonan
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Saito
authors.forename: Akio
authors.initials: A
authors.lastname: Suzuki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takaoka
authors.forename: Koji
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003486:Cyanides / Q000737:chemistry*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors; D017611:Fluorine Compounds / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; D003486:Cyanides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D017611:Fluorine Compounds; D007328:Insulin; D011480:Protease Inhibitors; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4