Design and synthesis of 3-pyridylacetamide derivatives as dipeptidyl peptidase IV (DPP-4) inhibitors targeting a bidentate interaction with Arg125

• Published in: Bioorganic & medicinal chemistry 2011-01, Vol.19 (1), p.172-185
• Main Authors: Miyamoto, Yasufumi, Banno, Yoshihiro, Yamashita, Tohru, Fujimoto, Tatsuhiko, Oi, Satoru, Moritoh, Yusuke, Asakawa, Tomoko, Kataoka, Osamu, Takeuchi, Koji, Suzuki, Nobuhiro, Ikedo, Koji, Kosaka, Takuo, Tsubotani, Shigetoshi, Tani, Akiyoshi, Funami, Miyuki, Amano, Michiko, Yamamoto, Yoshio, Aertgeerts, Kathleen, Yano, Jason, Maezaki, Hironobu
• Format: Article
• Language: English
• Subjects: Acetamides - chemistry; amino acids; Arginine - chemistry; Bidentate interaction; Biological and medical sciences; Crystallography, X-Ray; Dipeptidyl peptidase IV (DPP-4); dipeptidyl-peptidase IV; Dipeptidyl-Peptidase IV Inhibitors - chemistry; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Drug Design; General and cellular metabolism. Vitamins; hydrogen bonding; Medical sciences; Models, Molecular; niacin; Pharmacology. Drug treatments; Structure-Activity Relationship; Structure-based drug design (SBDD); X-radiation
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.11.038

Synthesis and biological evaluation of our dipeptidyl peptidase IV (DPP-4) inhibitor were performed, and compound 13j with the potent activity were identified. We have previously discovered nicotinic acid derivative 1 as a structurally novel dipeptidyl peptidase IV (DPP-4) inhibitor. In this study, we obtained the X-ray co-crystal structure between nicotinic acid derivative 1 and DPP-4. From these X-ray co-crystallography results, to achieve more potent inhibitory activity, we targeted Arg125 as a potential amino acid residue because it was located near the pyridine core, and some known DPP-4 inhibitors were reported to interact with this residue. We hypothesized that the guanidino group of Arg125 could interact with two hydrogen-bond acceptors in a bidentate manner. Therefore, we designed a series of 3-pyridylacetamide derivatives possessing an additional hydrogen-bond acceptor that could have the desired bidentate interaction with Arg125. We discovered the dihydrochloride of 1-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-(2-methylpropyl)pyridin-3-yl]acetyl}-l-prolinamide (13j) to be a potent and selective DPP-4 inhibitor that could interact with the guanidino group of Arg125 in a unique bidentate manner.