Discovery of Highly Polar β-Homophenylalanine Derivatives as Nonsystemic Intestine-Targeted Dipeptidyl Peptidase IV Inhibitors

Abstract

Although intensively expressed within intestine, the precise roles of intestinal dipeptidyl peptidase IV (DPPIV) in numerous pathologies remain incompletely understood. Here, we first reported a nonsystemic intestine-targeted (NSIT) DPPIV inhibitor with β-homophenylalanine scaffold, compound 7, which selectively inhibited the intestinal rather than plasmatic DPPIV at an oral dosage as high as 30 mg/kg. We expect that compound 7 could serve as a qualified tissue-selective tool to determine undetected physiological or pathological roles of intestinal DPPIV.

Trust Your Gut: Strategies and Tactics for Intestinally Restricted Drugs

“…In line with the examples previously described, Shen and coworkers recently reported an intestine-restricted dipeptidyl peptidase IV (DPP-4) inhibitor obtained through the attachment of a polar sulfonic acid fragment to a known systemic DPP-4 inhibitor. 27 As predicted, such structural modification led to a significant decrease in lipophilicity and consequently passive permeability, leading to low bioavailability in vivo. Selective inhibition of DPP-4 in the intestine versus plasma could potentially be exploited to gain a deeper understanding of the role of intestinal DPP-4 in a range of physiological processes.…”