- N-(4-acetamidophenyl)-5-acetylfuran-2-carboxamide as a novel orally available diuretic that targets urea transporters with improved PD and PK properties
-
Urea transporters (UTs) have been identified as new targets for diuretics. Functional deletion of UTs led to urea-selective urinary concentrating defects with relative salt sparing. In our previous study, a UT inhibitor with a diarylamide scaffold, which is denoted as 11a, was demonstrated as the first orally available UT inhibitor. However, the oral bioavailability of 11a was only 4.38%, which obstructed its clinical application. In this work, by replacing the nitro group of 11a with an acetyl group, 25a was obtained. Compared with 11a, 25a showed a 10 times stronger inhibitory effect on UT-B (0.14 μM vs. 1.41 μM in rats, and 0.48 μM vs. 5.82 μM in mice) and a much higher inhibition rate on UT-A1. Moreover, the metabolic stability both in vitro and in vivo and the drug-like properties (permeability and solubility) of 25a were obviously improved compared with those of 11a. Moreover, the bioavailability of 25a was 15.18%, which was 3 times higher than that of 11a, thereby resulting in significant enhancement of the diuretic activities in rats and mice. 25a showed excellent potential for development as a promising clinical diuretic candidate for targeting UTs to treat diseases that require long-term usage of diuretics, such as hyponatremia.
- Wang, Shuyuan,Xu, Yue,Zhao, Yan,Zhang, Shun,Li, Min,Li, Xiaowei,He, Jinzhao,Zhou, Hong,Ge, Zemei,Li, Runtao,Yang, Baoxue
-
-
- FIVE-MEMBERED HETEROCYCLIC DERIVATIVE, METHOD FOR PRODUCING SAME, AND PHARMACEUTICAL COMPOSITION COMPRISING SAME
-
The present invention relates to a five-membered heterocyclic compound having an analgesic effect and a pharmaceutical composition comprising a derivative of the five-membered heterocyclic compound. More specifically, the present invention relates to a me
- -
-
-
- Base-mediated decomposition of amide-substituted furfuryl tosylhydrazones: Synthesis and cytotoxic activities of enynyl-ketoamides
-
Base-mediated decomposition of amide-substituted furfuryl tosylhydrazones afforded practical access to novel multifunctionalized enynyl-ketoamides. In addition, furfuryl tosylhydrazones with stable furan rings underwent an interesting tosyl-group migratio
- Ji, Fanghua,Peng, Hui,Zhang, Xiaoting,Lu, Wenhua,Liu, Shubin,Jiang, Huanfeng,Liu, Bo,Yin, Biaolin
-
p. 2092 - 2102
(2015/04/21)
-
- A novel entry to spirofurooxindoles involving tandem dearomatization of furan ring and intramolecular friedel- Crafts reaction
-
A copper sulfate pentahydrate-catalyzed intramolecular Friedel-Crafts reaction using an oxocarbenium species derived from a furan ring as the alkylating agent was developed for the first time. By using this protocol, spirofurooxindoles 9 with multi-reactive sites were synthesized simply and concisely. In addition, selective hydrogenation of the endo-cyclic double bond and full hydrogenation of the endo and exo-cyclic double bonds of spirofurooxindoles 9 provided spirofurooxindoles 11 and 12, respectively. Copyright
- Yin, Biao-Lin,Lai, Jin-Qiang,Zhang, Ze-Ren,Jiang, Huan-Feng
-
supporting information; experimental part
p. 1961 - 1965
(2011/10/09)
-
- EP2 RECEPTOR AGONISTS
-
A compound of formula (III): or a salt, solvate and chemically protected form thereof, wherein: R5 is an optionally substituted C5-20 aryl or C4-20alkyl group; L′ is a single bond, —O— or —C(═O)—; A is selected from the group consisting of: formulae (i) (ii) (iii) wherein X and Y are selected from the group consisting of: O and CR3; S and CR3; NH and CR3; NH and N; O and N; S and N; N and S; and N and O, and where the dotted lines indicate a double bond in the appropriate location, and where Q is either N or CH; D is selected from: formulae (i) (ii) (iii) (iv) (v) (vii) (viii) (ix) B is selected from the group consisting of: formulae (A) (B) where RP6 is selected from fluoro and chloro; and R2 is either: (i) —CO2H; (ii) —CONH2; (iii) —CH2—OH; or (iv) tetrazol-5-yl.
- -
-
Page/Page column 20
(2010/06/14)
-