Journal of Medicinal Chemistry· 2026Q1
Structure-Guided Discovery of Orally Bioavailable Allosteric SLC6A19 Inhibitors that Promote Urinary Amino Acid Excretion In Vivo
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- Q1SCImago
- 2026year
Short summary
Researchers discovered compound 20, an orally bioavailable, allosteric inhibitor of the SLC6A19 transporter, which increases urinary amino acid excretion in vivo.
AI-generated from the title and abstract; the full text is not read.
Key points
- Compound 20 is a novel, orally bioavailable, allosteric inhibitor of the SLC6A19 transporter.
- Its discovery was guided by cryo-EM structures revealing two adjacent binding pockets.
- Oral dosing of compound 20 increased urinary amino acid excretion in mice and non-human primates.
- The inhibitor shows good potency against non-human primate SLC6A19, despite a ~10-fold shift against mouse SLC6A19.
AI-generated from the title and abstract; the full text is not read.
Abstract
Abstract SLC6A19 is a sodium-dependent transporter that mediates the absorption of neutral amino acids in the intestine and reabsorption of these amino acids in the kidney. Pharmacological inhibition of SLC6A19 may provide therapeutic benefit by normalizing plasma amino acid levels and potentially reducing renal tubular transport burden. Virtual screening against an allosteric binding pocket observed in the cryo-EM structure of SLC6A19/cinromide (1) identified compound 6 as a promising hit. The cryo-EM structure of SLC6A19/CB3 (2) revealed a second, partially overlapping pocket adjacent to the compound 6 binding site. Analogue design merging these two binding pockets followed by optimization led to compound 20, a potent, selective, and orally bioavailable allosteric SLC6A19 inhibitor. While compound 20 demonstrates an approximately 10-fold rightward potency shift against mouse SLC6A19, it retains good potency against non-human primate SLC6A19. Consistent with the SLC6A19 inhibition mechanism, oral dosing of 20 led to increased urinary amino acid excretion in a dose-dependent manner in human SLC6A19 knock-in mice and wild-type non-human primates.
The authors' abstract, as published at the source. Journal of Medicinal Chemistry, 2026 · DOI ↗
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Field: Biochemistry (Biochemistry, Genetics and Molecular Biology)
BiochemistryBiochemistry, Genetics and Molecular Biology