Structure-Guided Discovery of Orally Bioavailable Allosteric SLC6A19 Inhibitors that Promote Urinary Amino Acid Excretion In Vivo
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.
Authors
- Andre Shavnya
- Srinath Jagarlapudi
- Barbara L. Bernardo (ORCID: https://orcid.org/0009-0000-6272-4272)
- Magdalena Korczynska (ORCID: https://orcid.org/0000-0002-1339-5553)
- Jennifer Clemens
- Jason K. Dutra (ORCID: https://orcid.org/0000-0002-4563-5267)
- David Jon Wasilko (ORCID: https://orcid.org/0000-0002-6227-5902)
- Amy Thurber Moody (ORCID: https://orcid.org/0009-0007-3635-4088)
- Amanda King‐Ahmad
- Paula M. Loria (ORCID: https://orcid.org/0000-0003-4690-5991)
- Tristan S. Maurer (ORCID: https://orcid.org/0009-0007-2994-1954)
- Andrew J. Bessire
- Kimberly L. Steen
- Dianne Hernandez
- Vincent Mascitti
- Jamison B. Tuttle (ORCID: https://orcid.org/0009-0002-7201-7074)
- Joshua A. Lees (ORCID: https://orcid.org/0000-0001-7421-6881)
- Phillip Hudson
- Zachary Lee Johnson (ORCID: https://orcid.org/0000-0001-8954-0561)
- M. F. Sammons (ORCID: https://orcid.org/0000-0001-6472-0646)
- Nicholas Ferguson
- Matthew Dowling (ORCID: https://orcid.org/0000-0002-5140-764X)
- Ingrid A. Stock
- Denis Féliers (ORCID: https://orcid.org/0000-0003-1952-1386)
- Kevin D. Hesp (ORCID: https://orcid.org/0000-0002-3917-0547)
- Joseph Tillotson (ORCID: https://orcid.org/0000-0003-0795-5494)
- Steven COFFEY
- Huixian Wu (ORCID: https://orcid.org/0000-0003-1357-9747)
- John C. Murray (ORCID: https://orcid.org/0000-0002-1203-1192)
- David Hepworth (ORCID: https://orcid.org/0009-0009-6787-4662)
- Kari R. Fonseca
- Dahui Zhou (ORCID: https://orcid.org/0009-0007-9786-230X)
- Caroline A. Blakemore (ORCID: https://orcid.org/0000-0001-7055-6379)
- Andrew Fensome (ORCID: https://orcid.org/0000-0001-8916-1895)
- Amit S.S. Kalgutkar (ORCID: https://orcid.org/0000-0001-9701-756X)
- Lei Zhang (ORCID: https://orcid.org/0000-0001-8118-1402)
- Tao Wang (ORCID: https://orcid.org/0000-0003-1957-7160)
- Yuan Zhang (ORCID: https://orcid.org/0000-0002-3881-6537)
- Jun Xiao (ORCID: https://orcid.org/0009-0007-8649-8805)
- Melissa Avery
- Daniel Callahan
- Meihua Tu
- Wenzhe Ma
- Emily Jordan (ORCID: https://orcid.org/0009-0008-4392-2423)
- Robert Barnes
- Raman Sharma
- Jade Williams
- Jessica Ward
- Natalie Ochocki
- Ruth Sommese
- Janice Brown
- Rose Keenan
- Tracy Phillips
Institutions
- Pfizer (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-10-14
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c02154
- Primary Topic
- Amino Acid Enzymes and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00