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Bioorg Med Chem. 2015 Feb 15;23(4):779-90. doi: 10.1016/j.bmc.2014.12.051. Epub 2014 Dec 30.

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.

Author information

1
Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan. Electronic address: yohei-ikuma@ds-pharma.co.jp.
2
Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.

Abstract

We have previously reported a novel series of 3H-imidazo[4,5-c]quinolin-4(5H)-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 3H-imidazo[4,5-c]quinolin-4(5H)-ones using intramolecular radical cyclization.

KEYWORDS:

3H-Imidazo[4,5-c]quinolin-4(5H)-ones; Dipeptidyl peptidase IV; Prodrug; Type 2 diabetes mellitus

PMID:
25596166
DOI:
10.1016/j.bmc.2014.12.051
[Indexed for MEDLINE]

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