Discovery and Development of S6821 and S7958 as Potent TAS2R8 Antagonists

In humans, bitter
taste is mediated by 25 TAS2Rs. Many compounds,
including certain active pharmaceutical ingredients, excipients, and
nutraceuticals, impart their bitter taste (or in part) through TAS2R8
activation. However, effective TAS2R8 blockers that can either suppress
or reduce the bitterness of these compounds have not been described.
We are hereby reporting a series of novel 3-(pyrazol-4-yl) imidazolidine-2,4-diones
as potent and selective TAS2R8 antagonists. In human sensory tests, S6821 and S7958, two of the most potent analogues
from the series, demonstrated efficacy in blocking TAS2R8-mediated
bitterness and were selected for development. Following data evaluation
by expert panels of a number of national and multinational regulatory
bodies, including the US, the EU, and Japan, S6821 and S7958 were approved as safe under conditions of intended use
as bitter taste blockers.