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

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 18; pp. 5426 - 5430
• Main Authors: Peters, Jens-Uwe, Kühne, Holger, Dehmlow, Henrietta, Grether, Uwe, Conte, Aurelia, Hainzl, Dominik, Hertel, Cornelia, Kratochwil, Nicole A., Otteneder, Michael, Narquizian, Robert, Panousis, Constantinos G., Ricklin, Fabienne, Röver, Stephan
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.09.2010; Elsevier
• Subjects: Animals; Biological and medical sciences; Flushing; General and cellular metabolism. Vitamins; GPCR; GPR109A; GPR109B; Lead identification; Lipolysis; Medical sciences; Microsomes, Liver - metabolism; Niacin; Niacin - metabolism; Pharmacology. Drug treatments; Pyrido pyrimidinone; 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; Flushing; Lead identification; GPR109A; GPR109B; GPCR; Niacin; Lipolysis; Pyrido pyrimidinone; Nicotinic acid receptor; Agonist; Ether; Nitrogen heterocycle; Benzene derivatives; Lactam; Selectivity; In vitro; Structure activity relation; G protein coupled receptor; Bicyclic compound; Affinity; Fluorine Organic compounds; Chemical synthesis
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2010.07.108

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. 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.