AUTHOR=Yadav Aditya , Shah Nishank , Tiwari Praveen Kumar , Javed Kiran , Cheng Qi , Aidhen Indrapal Singh , Bröer Stefan 

TITLE=Novel Chemical Scaffolds to Inhibit the Neutral Amino Acid Transporter B0AT1 (SLC6A19), a Potential Target to Treat Metabolic Diseases

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00140

DOI=10.3389/fphar.2020.00140

ISSN=1663-9812

ABSTRACT=<p>Lack of B<sup>0</sup>AT1 (SLC6A19) partially protects mice against the onset of non-alcoholic steatohepatitis (NASH). To achieve a similar outcome through pharmacological treatment, we improved previously identified inhibitors of B<sup>0</sup>AT1 by medicinal chemistry and identified second generation inhibitors by high through-put screening. Modified diarylmethine compounds inhibited B<sup>0</sup>AT1 with IC<sub>50</sub> values ranging from 8–90 μM. A second generation of inhibitors was derived from high-throughput screening and showed higher affinity (IC<sub>50</sub> of 1–15 μM) and strong selectivity against amino acid transporters with similar substrate specificity, such as ASCT2 (SLC1A5) and LAT1 (SLC7A5). All compounds were unrelated to B<sup>0</sup>AT1 substrates, but were likely to bind in the vicinity of the substrate binding site.</p>