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

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.