title: Synthesis and structure-activity relationships of potent 3- or 4-substituted-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 degradation of glucagon-like peptide-1 (GLP-1) and extend its duration of action. A series of 2-cyanopyrrolidines are among the most potent of DPP-IV inhibitors. We focused our attention on substitutions at the 3- or 4-position of 2-cyanopyrrolidines and synthesized and evaluated various derivatives. Among them, the 4-fluoro derivative was found to exhibit better DPP-IV inhibitory activity and higher plasma drug concentrations after oral administration to rats than the 4-unsubstituted derivative. We report here on the synthesis and biological data of the aforementioned derivatives.
authors.affiliation: Medicinal Research 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: Masako
authors.initials: M
authors.lastname: Saito
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: D058892:Adenosine Deaminase Inhibitors; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4; D004791:Enzyme Inhibitors / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010599:Pharmacokinetics; D011759:Pyrrolidines / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D058892:Adenosine Deaminase Inhibitors; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D011759:Pyrrolidines; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4