Discovery of novel tricyclic full agonists for the G-protein-coupled niacin receptor 109A with minimized flushing in rats.

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Shen HC, Ding FX, Deng Q, Wilsie LC, Krsmanovic ML, Taggart AK, Carballo-Jane E, Ren N, Cai TQ, Wu TJ, Wu KK, Cheng K, Chen Q, Wolff MS, Tong X, Holt TG, Waters MG, Hammond ML, Tata JR, Colletti SL

Discovery of novel tricyclic full agonists for the G-protein-coupled niacin receptor 109A with minimized flushing in rats.

J Med Chem. 2009 Apr 23;52(8):2587-602. doi: 10.1021/jm900151e.

PubMed ID

19309152 [ View in PubMed

]

Abstract

Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction and vasodilation effects in rats, with very weak cytochrome P450 2C8 (CYP2C8) and cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Niacin	Hydroxycarboxylic acid receptor 2	EC 50 (nM)	1000	N/A	N/A	Details
Niacin	Hydroxycarboxylic acid receptor 2	IC 50 (nM)	140	N/A	N/A	Details