Rational design and synthesis of potent and long-lasting glutamic acid-based dipeptidyl peptidase IV inhibitors

A series of (2 S)-cyanopyrrolidines with glutamic acid derivatives at the P2 site have been prepared and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV). The structure–activity relationships (SAR) led to the discovery of potent 3-substituted glutamic acid analogues, providing enhanced ch...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-04, Vol.19 (7), p.1908-1912
Main Authors: Tsai, Ting-Yueh, Hsu, Tsu, Chen, Chiung-Tong, Cheng, Jai-Hong, Chiou, Mei-Chun, Huang, Chih-Hsiang, Tseng, Ya-Ju, Yeh, Teng-Kuang, Huang, Chung-Yu, Yeh, Kai-Chia, Huang, Yu-Wen, Wu, Ssu-Hui, Wang, Min-Hsien, Chen, Xin, Chao, Yu-Sheng, Jiaang, Weir-Torn
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Biological and medical sciences
Dipeptidyl Peptidase 4 - blood
Dipeptidyl Peptidase 4 - metabolism
Dipeptidyl-Peptidase IV Inhibitors - chemical synthesis
Dipeptidyl-Peptidase IV Inhibitors - chemistry
Dipeptidyl-Peptidase IV Inhibitors - pharmacology
DPP-IV
Drug Design
General and cellular metabolism. Vitamins
Glucose - metabolism
Glutamic acid
Glutamic Acid - chemistry
Inhibitor
Medical sciences
Mice
Mice, Inbred C57BL
Pharmacology. Drug treatments
Pyrrolidines - chemical synthesis
Pyrrolidines - chemistry
Pyrrolidines - pharmacology
Structure-Activity Relationship
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Summary:A series of (2 S)-cyanopyrrolidines with glutamic acid derivatives at the P2 site have been prepared and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV). The structure–activity relationships (SAR) led to the discovery of potent 3-substituted glutamic acid analogues, providing enhanced chemical stability and excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. Compound 13f exhibited the ability to both significantly decrease the glucose excursion and inhibit plasma DPP-IV activity.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.02.061