Synthesis and biological activity of sulphostin analogues, novel dipeptidyl peptidase IV inhibitors

• Published in: Bioorganic & medicinal chemistry 2005-02, Vol.13 (3), p.785-797
• Main Authors: Abe, Masatoshi, Akiyama, Tetsuo, Umezawa, Yōji, Yamamoto, Keiichiro, Nagai, Masashi, Yamazaki, Hiroko, Ichikawa, Yuh-ichiro, Muraoka, Yasuhiko
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Dipeptidyl Peptidase 4 - drug effects; Dipeptidyl peptidase IV inhibitors; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Kidney - enzymology; Magnetic Resonance Spectroscopy; Medical sciences; Miscellaneous; Organophosphorus Compounds - chemical synthesis; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - pharmacology; Pharmacology. Drug treatments; Piperidones - chemical synthesis; Piperidones - chemistry; Piperidones - pharmacology; Rats; Structure–activity relationships; Sulphostin analogues
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2004.10.036

The required structure of sulphostin analogues for the dipeptidyl peptidase IV inhibitory activity. n = 1−3, R = H or SO 3H; Sulphostin: n = 2, R = SO 3H. The structure of sulphostin ( 1), a novel dipeptidyl peptidase IV (DPP-IV) inhibitor, is consisted of three key functional groups, including a characteristic amino(sulfoamino)phosphinyl group, on a piperidine ring. To examine the relationship between its structure and the inhibitory activity against DPP-IV, various analogues were synthesized and their activities were investigated. These results indicated that all of the functional groups on the piperidine ring were crucial to the DPP-IV inhibitory activity of sulphostin, and that the sulfonic acid group, which constructed the amino(sulfoamino)phosphinyl group, contributed to the stability of the compound. Moreover, those functional groups should be adjoined on the piperidine ring for the inhibitory activity. The size of the nitrogen-containing heterocyclic ring including piperidine appeared to scarcely affect the activity. In the present study, the sulfonic acid-deficient five-membered ring analogue 27a showed the strongest inhibitory activity (IC 50 = 11 nM).