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

ABSTRACT: Lack of B0AT1 (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 B0AT1 by medicinal chemistry and identified second generation inhibitors by high through-put screening. Modified diarylmethine compounds inhibited B0AT1 with IC50 values ranging from 8-90 ?M. A second generation of inhibitors was derived from high-throughput screening and showed higher affinity (IC50 of 1-15 ?M) and strong selectivity against amino acid transporters with similar substrate specificity, such as ASCT2 (SLC1A5) and LAT1 (SLC7A5). All compounds were unrelated to B0AT1 substrates, but were likely to bind in the vicinity of the substrate binding site.

SUBMITTER: Yadav A

PROVIDER: S-EPMC7059793 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Yadav Aditya A Shah Nishank N Tiwari Praveen Kumar PK Javed Kiran K Cheng Qi Q Aidhen Indrapal Singh IS Bröer Stefan S

Frontiers in pharmacology 20200228

Lack of B0AT1 (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 B0AT1 by medicinal chemistry and identified second generation inhibitors by high through-put screening. Modified diarylmethine compounds inhibited B0AT1 with IC50 values ranging from 8-90 μM. A second generation of inhibitors was derived ...[more]

PMID: 32180718

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