Discovery and Optimization of Novel SUCNR1 Inhibitors: Design of Zwitterionic Derivatives with a Salt Bridge for the Improvement of Oral Exposure

G-protein-coupled receptor SUCNR1
(succinate receptor 1 or GPR91)
senses the citric cycle intermediate succinate and is implicated in
various pathological conditions such as rheumatoid arthritis, liver
fibrosis, or obesity. Here, we describe a novel SUCNR1 antagonist
scaffold discovered by high-throughput screening. The poor permeation
and absorption properties of the most potent compounds, which were
zwitterionic in nature, could be improved by the formation of an internal
salt bridge, which helped in shielding the two opposite charges and
thus also the high polarity of zwitterions with separated charges.
The designed compounds containing such a salt bridge reached high
oral bioavailability and oral exposure. We believe that this principle
could find a broad interest in the medicinal chemistry field as it
can be useful not only for the modulation of properties in zwitterionic
compounds but also in acidic or basic compounds with poor permeation.