Synthesis and structure-activity relationships of potent 1-(2-substituted-aminoacetyl)-4-fluoro-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors.
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.
Fukushima
Hiroshi
H
Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, Saitama, Japan. hiroshi.fukushima@po.rd.taisho.co.jp
Hiratate
Akira
A
Takahashi
Masato
M
Saito-Hori
Masako
M
Munetomo
Eiji
E
Kitano
Kiyokazu
K
Saito
Hidetaka
H
Takaoka
Yuji
Y
Yamamoto
Koji
K
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
D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D011392:Proline; D014633:Valine