Discovery of 3H-imidazo[4, 5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors: Use of a carboxylate prodrug to improve bioavailability. Issue 4 (15th February 2015)

• Record Type: Journal Article
• Authors: Ikuma, Yohei; Hochigai, Hitoshi; Kimura, Hidenori; Nunami, Noriko; Kobayashi, Tomonori; Uchiyama, Katsuya; Umezome, Takashi; Sakurai, Yasumitsu; Sawada, Naoyuki; Tadano, Jun; Sugaru, Eiji; Ono, Michiko; Hirose, Yuko; Nakahira, Hiroyuki
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 4(2015)
• Page Start: 779
• Page End: 790
• Publication Date: 2015-02-15
• Subjects: Dipeptidyl peptidase IV -- Type 2 diabetes mellitus -- 3H-Imidazo[4, 5-c]quinolin-4(5H)-ones -- Prodrug; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2014.12.051
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: We have previously reported a novel series of 3 H -imidazo[4, 5- c ]quinolin-4(5 H )-ones with potent dipeptidyl peptidase IV (DPP-4) inhibitory activity. However, these compounds showed poor oral absorption. We attempted in this study esterification of the carboxylic acid moiety to improve the compounds 1 –4 plasma concentrations. Our efforts yielded 10h with a 5-methyl-2-oxo-1, 3-dioxol-4-yl methyl ester as an S9/plasma-cleavable functionality. Compound 10h showed significantly high oral absorption and potent DPP-4 inhibition in vivo and decreased Zucker fatty rats glucose levels in the oral glucose tolerance test. Optimization of the ester moiety revealed that rapid conversion to the carboxyl form in both liver S9 fractions and serum was important for prodrugs not to be detected in the plasma after oral administration. In particular, lability in the serum was found to be an important characteristic. Through our investigation, we were able to develop a novel efficient synthetic method for construction of 3 H -imidazo[4, 5- c ]quinolin-4(5 H )-ones using intramolecular radical cyclization.