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

  • J Med Chem. 2023 Mar 9;66(5):3499-3521. doi: 10.1021/acs.jmedchem.2c01997.
Lukas Waterloo  1 ,  Harald Hübner  1 ,  Fabrizio Fierro  2 ,  Tara Pfeiffer  1 ,  Regine Brox  1 ,  Stefan Löber  1 ,  Dorothee Weikert  1 ,  Masha Y Niv  2 ,  Peter Gmeiner  1
Affiliations
  • 1. Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nikolaus-Fiebiger-Str. 10, Erlangen 91058, Germany.
  • 2. The Robert H. Smith Faculty of Agriculture, Food and Environment, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University, Rehovot 7610001, Israel.
PMID: 36847646 DOI: 10.1021/acs.jmedchem.2c01997
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.

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