Novel series of 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides as potent and selective dipeptidyl peptidase IV inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2012-12, Vol.22 (23), p.7036-7040
• Main Authors: Nitta, Aiko, Fujii, Hideaki, Sakami, Satoshi, Satoh, Mikiya, Nakaki, Junko, Satoh, Shiho, Kumagai, Hiroki, Kawai, Hideki
• Format: Article
• Language: English
• Subjects: Administration, Oral; Amides - chemical synthesis; Amides - chemistry; Amides - metabolism; Animals; Biological and medical sciences; Blood; blood glucose; Blood Glucose - metabolism; Caco-2 Cells; CD26 antigen; chemistry; Diabetes; Dipeptidyl Peptidase 4 - blood; Dipeptidyl Peptidase 4 - chemistry; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl peptidase IV; Dipeptidyl-Peptidase IV Inhibitors - chemical synthesis; Dipeptidyl-Peptidase IV Inhibitors - chemistry; Dipeptidyl-Peptidase IV Inhibitors - metabolism; Glucose tolerance; Glucose Tolerance Test; glucose tolerance tests; Humans; Inhibitor; Medical sciences; Mice; Mice, Inbred ICR; Oral administration; Pharmacology. Drug treatments; Protein Binding; Pyrans - chemical synthesis; Pyrans - chemistry; Pyrans - metabolism; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - metabolism
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.09.099

A series of novel 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides were investigated as dipeptidyl peptidase IV (DPP-4) inhibitors. Introduction of a 4-phenylthiazol-2-yl group showed highly potent DPP-4 inhibitory activity. Among various derivatives, (3R)-3-amino-N-(4-(4-phenylthiazol-2-yl)-tetrahydro-2H-thiopyran-4-yl)-4-(2,4,5-trifluorophenyl)butanamide 1,1-dioxide (30) reduced blood glucose excursion in an oral glucose tolerance test by oral administration.