Pyrido pyrimidinones as selective agonists of the high affinity niacin receptor GPR109A: optimization of in vitro activity

Jens-Uwe Peters; Holger Kühne; Henrietta Dehmlow; Uwe Grether; Aurelia Conte; Dominik Hainzl; Cornelia Hertel; Nicole A Kratochwil; Michael Otteneder; Robert Narquizian; Constantinos G Panousis; Fabienne Ricklin; Stephan Röver

doi:10.1016/j.bmcl.2010.07.108

Pyrido pyrimidinones as selective agonists of the high affinity niacin receptor GPR109A: optimization of in vitro activity

Bioorg Med Chem Lett. 2010 Sep 15;20(18):5426-30. doi: 10.1016/j.bmcl.2010.07.108. Epub 2010 Jul 29.

Authors

Jens-Uwe Peters¹, Holger Kühne, Henrietta Dehmlow, Uwe Grether, Aurelia Conte, Dominik Hainzl, Cornelia Hertel, Nicole A Kratochwil, Michael Otteneder, Robert Narquizian, Constantinos G Panousis, Fabienne Ricklin, Stephan Röver

Affiliation

¹ Pharma Research, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.

PMID: 20724150
DOI: 10.1016/j.bmcl.2010.07.108

Abstract

Pyrido pyrimidinones are selective agonists of the human high affinity niacin receptor GPR109A (HM74A). They show no activity on the highly homologous low affinity receptor GPR109B (HM74). Starting from a high throughput screening hit the in vitro activity of the pyrido pyrimidinones was significantly improved providing lead compounds suitable for further optimization.

MeSH terms

Animals
Microsomes, Liver / metabolism
Niacin / metabolism*
Pyrimidinones / administration & dosage
Pyrimidinones / chemistry*
Pyrimidinones / metabolism
Pyrimidinones / pharmacology*
Rats
Rats, Wistar
Receptors, G-Protein-Coupled / agonists*
Receptors, G-Protein-Coupled / metabolism*
Receptors, Nicotinic / metabolism*
Structure-Activity Relationship

Substances

HCAR2 protein, human
Hcar2 protein, rat
Pyrimidinones
Receptors, G-Protein-Coupled
Receptors, Nicotinic
Niacin