In vitro safety signals for potential clinical development of the anti-inflammatory pregnane X receptor agonist FKK6
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F24%3A73625408" target="_blank" >RIV/61989592:15110/24:73625408 - isvavai.cz</a>
Alternative codes found
RIV/61989592:15640/24:73625408 RIV/61989592:15310/24:73625408 RIV/00027006:_____/24:10177145
Result on the web
<a href="https://www.sciencedirect.com/science/article/pii/S0045206824000427" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0045206824000427</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.bioorg.2024.107137" target="_blank" >10.1016/j.bioorg.2024.107137</a>
Alternative languages
Result language
angličtina
Original language name
In vitro safety signals for potential clinical development of the anti-inflammatory pregnane X receptor agonist FKK6
Original language description
Based on the mimicry of microbial metabolites, functionalized indoles were demonstrated as the ligands and agonists of the pregnane X receptor (PXR). The lead indole, FKK6, displayed PXR-dependent protective effects in DSS-induced colitis in mice and in vitro cytokine-treated intestinal organoid cultures. Here, we report on the initial in vitro pharmacological profiling of FKK6. FKK6-PXR interactions were characterized by hydrogen–deuterium exchange mass spectrometry. Screening FKK6 against potential cellular off-targets (G protein-coupled receptors, steroid and nuclear receptors, ion channels, and xenobiotic membrane transporters) revealed high PXR selectivity. FKK6 has poor aqueous solubility but was highly soluble in simulated gastric and intestinal fluids. A large fraction of FKK6 was bound to plasma proteins and chemically stable in plasma. The partition coefficient of FKK6 was 2.70, and FKK6 moderately partitioned into red blood cells. In Caco2 cells, FKK6 displayed high permeability (A-B: 22.8 × 10–6 cm.s−1) and no active efflux. These data are indicative of essentially complete in vivo absorption of FKK6. The data from human liver microsomes indicated that FKK6 is rapidly metabolized by cytochromes P450 (t1/2 5 min), notably by CYP3A4. Two oxidized FKK6 derivatives, including DC73 (N6-oxide) and DC97 (C19-phenol), were detected, and these metabolites had 5–7 × lower potency as PXR agonists than FKK6. This implies that despite high intestinal absorption, FKK6 is rapidly eliminated by the liver, and its PXR effects are predicted to be predominantly in the intestines. In conclusion, the PXR ligand and agonist FKK6 has a suitable pharmacological profile supporting its potential preclinical development.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
<a href="/en/project/GA22-00355S" target="_blank" >GA22-00355S: Pharmacological mimicry of microbial metabolites in the modulation of intestinal health</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
BIOORGANIC CHEMISTRY
ISSN
0045-2068
e-ISSN
1090-2120
Volume of the periodical
144
Issue of the periodical within the volume
MAR
Country of publishing house
US - UNITED STATES
Number of pages
12
Pages from-to
"107137-1107137"-"1107137-12"
UT code for WoS article
001167691400001
EID of the result in the Scopus database
2-s2.0-85183622015