Related Experiment Video

Updated: Jan 21, 2026

Detection of Viruses from Bioaerosols Using Anion Exchange Resin
06:10

Detection of Viruses from Bioaerosols Using Anion Exchange Resin

Published on: August 22, 2018

8.6K

4,8-Dimethylcoumarin Inhibitors of Intestinal Anion Exchanger slc26a3 (Downregulated in Adenoma) for Anti-Absorptive

Sujin Lee, Onur Cil, Peter M Haggie

    Journal of Medicinal Chemistry
    |August 8, 2019
    PubMed

    Insights

    New 4,8-dimethylcoumarin analogues effectively inhibit the SLC26A3 chloride/bicarbonate exchanger, showing promise for treating constipation. Compound 4az demonstrated potent inhibition and normalized stool water content in mice.

    Area of Science:

    • Biochemistry
    • Pharmacology
    • Gastroenterology

    Background:

    • The SLC26A3 chloride/bicarbonate exchanger in colonic epithelium is crucial for stool dehydration.
    • Inhibition of SLC26A3 is a potential therapeutic strategy for constipation, including that linked to cystic fibrosis.

    Purpose of the Study:

    • To synthesize and evaluate novel 4,8-dimethylcoumarin analogues as inhibitors of the SLC26A3 exchanger.
    • To identify potent and pharmacokinetically suitable SLC26A3 inhibitors for preclinical development.

    Main Methods:

    • Synthesis of a focused library of 4,8-dimethylcoumarin analogues.
    • Structure-activity relationship studies to determine key active moieties.
    • In vitro inhibition assays (IC50 determination) and in vivo pharmacokinetic and efficacy studies in mouse models.

    Main Results:

    • Identified 4,8-dimethylcoumarin-3-acetic acid as essential for activity.
    • Discovered potent inhibitors, including 3-iodo- (4az) and 3-trifluoromethyl- (4be) analogues, with IC50 values as low as 25 nM.
    • Demonstrated favorable pharmacokinetics for 4az, achieving therapeutic concentrations for over 72 hours after a single oral dose.
    • 4az normalized stool water content in a loperamide-induced constipation mouse model at 10 mg/kg.

    Conclusions:

    • Novel 4,8-dimethylcoumarin analogues, particularly 4az, exhibit potent SLC26A3 inhibition.
    • Compound 4az possesses favorable pharmacological properties and efficacy in a preclinical constipation model.
    • 4az warrants further investigation for its potential as a constipation therapeutic agent.

    More Related Videos

    Purification of Extracellular Trypanosomes, Including African, from Blood by Anion-Exchangers Diethylaminoethyl-cellulose Columns14:26

    Purification of Extracellular Trypanosomes, Including African, from Blood by Anion-Exchangers Diethylaminoethyl-cellulose Columns

    Published on: April 6, 2019

    10.7K
    Author Spotlight: Exploring Non-Motor Symptoms in Parkinson's Disease03:20

    Author Spotlight: Exploring Non-Motor Symptoms in Parkinson's Disease

    Published on: September 22, 2023

    2.3K

    Related Concept Videos

    Glucose Absorption Into the Small Intestine01:26

    Glucose Absorption Into the Small Intestine

    Complex carbohydrates consumed cannot be absorbed into the small intestine in their original form. First, they must be hydrolyzed to a monosaccharide form such as glucose or galactose. These monosaccharides are then transported across the intestinal membrane and into the blood via transcellular transport. The intestinal epithelial cells allow the movement of these monosaccharides with a defined 'entry' through membrane transporter proteins present on their apical membrane and...
    35.2K
    Receptor Downregulation in MVBs01:15

    Receptor Downregulation in MVBs

    Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
    The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
    2.8K
    Social Exchange Theory02:06

    Social Exchange Theory

    We have discussed why we form relationships, what attracts us to others, and different types of love. But what determines whether we are satisfied with and stay in a relationship? One theory that provides an explanation is social exchange theory. According to social exchange theory, we act as naïve economists in keeping a tally of the ratio of costs and benefits of forming and maintaining a relationship with others (Rusbult & Van Lange, 2003).
    39.5K
    Gas Exchange and Transport01:20

    Gas Exchange and Transport

    Gas exchange, the intake of molecular oxygen (O2) from the environment and the outflow of carbon dioxide (CO2) into the environment, is necessary for cellular function. Gas exchange during respiration occurs largely via the movement of gas molecules along pressure gradients. Gas travels from areas of higher partial pressure to areas of lower partial pressure. In mammals, gas exchange occurs in the alveoli of the lungs, which are adjacent to capillaries and share a membrane with them.
    76.6K
    Eukaryotic Transcription Inhibitors01:52

    Eukaryotic Transcription Inhibitors

    Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
    Eukaryotic transcription inhibitors usually contain two distinct domains, a...
    10.9K
    Drug Absorption: Factors Affecting GI Absorption01:19

    Drug Absorption: Factors Affecting GI Absorption

    The process of oral drug absorption can be influenced by several factors. Weakly acidic drugs tend to be absorbed more readily from the stomach due to their nonionized state. However, absorption may be less efficient in the upper intestine, where drugs are often ionized. Interestingly, despite the stomach's apparent advantage for drug absorption, its mucous layer can hinder diffusion. Its surface area is also smaller than the intestine's, which can further slow down the absorption rate.
    6.1K