Discovery of 2-Aminopyrimidines as Potent Agonists for the Bitter Taste Receptor TAS2R14

Lukas Waterloo, Harald Hübner, Fabrizio Fierro, Tara Pfeiffer, Regine Brox, Stefan Löber, Dorothee Weikert, Masha Y. Niv*, Peter Gmeiner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The bitter taste receptor TAS2R14 is a G protein-coupled receptor that is found on the tongue as well as in the human airway smooth muscle and other extraoral tissues. Because its activation causes bronchodilatation, TAS2R14 is a potential target for the treatment of asthma or chronic obstructive pulmonary disease. Structural variations of flufenamic acid, a nonsteroidal anti-inflammatory drug, led us to 2-aminopyridines showing considerable efficacy and potency in an IP1accumulation assay. In combination with an exchange of the carboxylic moiety by a tetrazole unit, a set of promising new TAS2R14 agonists was developed. The most potent ligand 28.1 (EC50 = 72 nM) revealed a six-fold higher potency than flufenamic acid and a maximum efficacy of 129%. Besides its unprecedented TAS2R14 activation, 28.1 revealed marked selectivity over a panel of 24 non-bitter taste human G protein-coupled receptors.

Original languageAmerican English
Pages (from-to)3499-3521
Number of pages23
JournalJournal of Medicinal Chemistry
Volume66
Issue number5
DOIs
StatePublished - 9 Mar 2023

Bibliographical note

Funding Information:
This work was supported by the German Research Foundation (DFG, Gm13/12–1 to P.G. and M.Y.N.).

Publisher Copyright:
© 2023 American Chemical Society.

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