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

Author: 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

Description: 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.

Subject headings: Acetamides; Arginine; Crystallography, X-Ray; Dipeptidyl-Peptidase IV Inhibitors; Drug Design; Models, Molecular; Structure-Activity Relationship

Publication year: 2011

Journal or book title: Bioorganic & Medicinal Chemistry

Volume: 19

Issue: 1

Pages: 172-185

Find the full text:

Find more like this one (cited by):,26&sciodt=0,26&hl=en

Serial number: 3348

Leave a Reply

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.