Synthesis and structure-activity relationships of potent 4-fluoro-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors

  • Bioorg Med Chem. 2008 Apr 1;16(7):4093-106. doi: 10.1016/j.bmc.2008.01.016.
Hiroshi Fukushima  1 ,  Akira Hiratate ,  Masato Takahashi ,  Ayako Mikami ,  Masako Saito-Hori ,  Eiji Munetomo ,  Kiyokazu Kitano ,  Sumi Chonan ,  Hidetaka Saito ,  Akio Suzuki ,  Yuji Takaoka ,  Koji Yamamoto
Affiliations
  • 1. Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403, Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan. [email protected]
PMID: 18243000 DOI: 10.1016/j.bmc.2008.01.016
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.

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