Carboxylic Acid Bioisosteres of Creatine as Novel and Selective Substrate Competitive Inhibitors of the Creatine Transporter SLC6A8

  • J Med Chem. 2026 Feb 26;69(4):3915-3931. doi: 10.1021/acs.jmedchem.5c02607.
Eduardo J Martinez  1 ,  Darren H Wong  1 ,  Amish J Patel  1 ,  Roy J Vaz  2 ,  Robert W Busby  1 ,  Robert Zahler  1 ,  Daniel Schefer  1 ,  Hui Zhao  3 ,  Xiaoming Xu  3 ,  Zizhao Liu  3 ,  Ruifang Meng  3 ,  Bernd Kaiser  4 ,  Jianchao Liu  3 ,  Lei Wen  3 ,  Rui Liu  3 ,  Katya Leites  1 ,  Helen S Tian  5 ,  Sohail F Tavazoie  5 ,  Masoud F Tavazoie  1 ,  Isabel Kurth  1
Affiliations
  • 1. Inspirna, Inc.30-02 48th Avenue, Suite 350, Long Island City, New York 11101, United States.
  • 2. Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, California 94158, United States.
  • 3. Pharmaron Beijing Co., Ltd. 6, Taihe Road, BDA, Beijing 100176, P.R. of China.
  • 4. Escientia Life Sciences, LLC, 250 Nutmeg Road South, Unit N, South Windsor, Connecticut 06074, United States.
  • 5. The Rockefeller University1230 York Ave, New York, New York 10065, United States.
PMID: 41649519 DOI: 10.1021/acs.jmedchem.5c02607
Abstract

Creatine, a naturally occurring guanidine carboxylic acid, serves as a critical energy metabolite in tissues with high energy demands. Certain cancers upregulate creatine metabolism to supplement their energy needs. Ompenaclid, a salt form of the well-studied creatine transporter inhibitor 3-guanidinopropionic acid (β-GPA), is in clinical development for the treatment of patients with colorectal tumors. Existing SLC6A8 inhibitors are low-potency molecules and frequently interact with related transporters. Herein, we report the discovery of SLC6A8 inhibitors with increased selectivity as well as in vitro and in vivo potency. A bioisostere approach was used by replacing the carboxylic acid of β-GPA with surrogate functional groups to achieve these improvements. Docking of these inhibitors into the recently published SLC6A8 cryo-EM structure reveals key binding contacts and supports the observed structure-activity relationships.

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