Design and synthesis of DPP-IV inhibitors lacking the electrophilic nitrile group

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• 作者：Takashi Kondo ; Takahiro Nekado ; Isamu Sugimoto ; Kenya Ochi ; Shigeyuki Takai ; Atsushi Kinoshita ; Akira Hatayama ; Susumu Yamamoto ; Katsuya Kishikawa ; Hisao Nakai ; Masaaki Toda
• 关键词：DPP-IV inhibitor ; (4β ; -Substituted)-l-prolylpyrrolidine ; 1 ; 2 ; 4-Thiadiazol-5-yl-piperazine
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 出版时间：15 February 2008
• 年：2008
• 卷：16
• 期：4
• 页码：1613-1631
• 全文大小：348 K

文摘

A series of (4β-substituted)-l-prolylpyrrolidine analogs lacking the electrophilic nitrile function were synthesized and their dipeptidyl peptidase IV (DPP-IV) inhibitory activity and duration of ex vivo activity were evaluated. Structural optimization of a N-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine analog 8, which was found by high-speed analog synthesis, was carried out to improve the potency and duration of action. A representative compound 26 was evaluated to assess its effect on the plasma glucose level after the oGTT (oral glucose tolerance test) in normal rats. Structure–activity relationships (SAR) are also presented.