Fukushima Hiroshi, Hiratate Akira, Takahashi Masato, Saito Masako, Munetomo Eiji, Kitano Kiyokazu, Saito Hidetaka, Takaoka Yuji, Yamamoto Koji
Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
Bioorg Med Chem. 2004 Dec 1;12(23):6053-61. doi: 10.1016/j.bmc.2004.09.010.
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.
二肽基肽酶IV（DPP-IV）抑制剂作为治疗2型糖尿病的潜在药物受到关注，因为它们可防止胰高血糖素样肽-1（GLP-1）降解并延长其作用持续时间。一系列2-氰基吡咯烷是最有效的DPP-IV抑制剂之一。我们将注意力集中在2-氰基吡咯烷的3-位或4-位取代上，合成并评估了各种衍生物。其中，发现4-氟衍生物比4-未取代衍生物在对大鼠口服给药后表现出更好的DPP-IV抑制活性和更高的血浆药物浓度。我们在此报告上述衍生物的合成及生物学数据。
