Novel Chemical Scaffolds to Inhibit the Neutral Amino Acid Transporter B 0AT1 (SLC6A19), a Potential Target to Treat Metabolic Diseases

摘要

Lack of B ~(0)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 ~(0)AT1 by medicinal chemistry and identified second generation inhibitors by high through-put screening. Modified diarylmethine compounds inhibited B ~(0)AT1 with IC _(50) values ranging from 8–90 μM. A second generation of inhibitors was derived from high-throughput screening and showed higher affinity (IC _(50) 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 ~(0)AT1 substrates, but were likely to bind in the vicinity of the substrate binding site.