TY - JOUR
T1 - Discovery of 2-Aminopyrimidines as Potent Agonists for the Bitter Taste Receptor TAS2R14
AU - Waterloo, Lukas
AU - Hübner, Harald
AU - Fierro, Fabrizio
AU - Pfeiffer, Tara
AU - Brox, Regine
AU - Löber, Stefan
AU - Weikert, Dorothee
AU - Niv, Masha Y.
AU - Gmeiner, Peter
N1 - Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/3/9
Y1 - 2023/3/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85149906320&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.2c01997
DO - 10.1021/acs.jmedchem.2c01997
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 36847646
AN - SCOPUS:85149906320
SN - 0022-2623
VL - 66
SP - 3499
EP - 3521
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -
