title: 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.
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.
authors.affiliation: 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.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Ikuma
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hochigai
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Nunami
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Uchiyama
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Umezome
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Sakurai
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Sawada
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Tadano
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Sugaru
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Ono
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hirose
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakahira
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008958:Models, Molecular; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011804:Quinolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007093:Imidazoles; D011355:Prodrugs; D011804:Quinolines; D018819:Dipeptidyl Peptidase 4
keywords: 3H-Imidazo[4,5-c]quinolin-4(5H)-ones; Dipeptidyl peptidase IV; Prodrug; Type 2 diabetes mellitus