Microbial metabolite mimicry is a new concept that promises to deliver compounds that have minimal liabilities and enhanced therapeutic effects in a host. In a previous publication, we have shown that microbial metabolites of L-tryptophan, indoles, when chemically altered, yielded potent anti-inflammatory pregnane X Receptor (PXR)-targeting lead compounds, FKK5 and FKK6, targeting intestinal inflammation. Our aim in this study was to further define structure-activity relationships between indole analogs and PXR, we removed the phenyl-sulfonyl group or replaced the pyridyl residue with imidazolopyridyl of FKK6. Our results showed that while removal of the phenyl-sulfonyl group from FKK6 (now called CVK003) shifts agonist activity away from PXR towards the aryl hydrocarbon receptor (AhR), the imidazolopyridyl addition preserves PXR activity in vitro. However, when these compounds are administered to mice, that unlike the parent molecule, FKK6, they exhibit poor induction of PXR target genes in the intestines and the liver. These data suggest that modifications of FKK6 specifically in the pyridyl moiety can result in compounds with weak PXR activity in vivo. These observations are a significant step forward for understanding the structure-activity relationships (SAR) between indole mimics and receptors, PXR and AhR.

Department of Anatomy and Structural Biology Albert Einstein College of Medicine Bronx NY USA

Department of Biochemistry Albert Einstein College of Medicine Bronx NY USA

Department of Cell Biology and Genetics Faculty of Science Palacký University Šlechtitelů 27 783 71 Olomouc Czech Republic

Department of Medical Education Albert Einstein College of Medicine Bronx NY USA

Department of Medicine and Genetics Albert Einstein College of Medicine Bronx NY USA

Department of Pathology Albert Einstein College of Medicine Bronx NY USA

Department of Pathology Albert Einstein College of Medicine Bronx NY USA; Department of Pathology University of Chicago Chicago IL USA

Shanghai University of Traditional Chinese Medicine Shanghai China

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