title: Discovery of 4-(phenyl)thio-1H-pyrazole derivatives as agonists of GPR109A, a high affinity niacin receptor.
abstract: Even though nicotinic acid (niacin) appears to have beneficial effects on human lipid profiles, niacin-induced cutaneous vasodilatation called flushing limits its remedy to patient. GPR109A is activated by niacin and mediates the anti-lipolytic effects. Based on the hypothesis that β-arrestin signaling mediates niacin-induced flushing, but not its anti-lipolytic effect, we tried to find GPR109A agonists which selectively elicit Gi-protein-biased signaling devoid of β-arrestin internalization using a β-lactamase assay. We identified a 4-(phenyl)thio-1H-pyrazole as a novel scaffold for GPR109A agonist in a high throughput screen, which has no carboxylic acid moiety known to be important for binding. While 1-nicotinoyl derivatives (5a-g, 6a-e) induced β-arrestin recruitment, 1-(pyrazin-2-oyl) derivatives were found to play as G-protein-biased agonists without GPR109A receptor internalization. The activity of compound 5a (EC50 = 45 nM) was similar to niacin (EC50 = 52 nM) and MK-6892 (EC50 = 74 nM) on calcium mobilization assay, but its activity at 10 μM on β-arrestin recruitment were around two and five times weaker than niacin and MK-6892, respectively. The development of G-protein biased GPR109A ligands over β-arrestin pathway is attainable and might be important in differentiation of pharmacological efficacy.
authors.affiliation: Research Center for Drug Discovery Technology, Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong, Daejeon, 305-343, Republic of Korea.
authors.forename: Hyeon Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Vithal B
authors.initials: VB
authors.lastname: Jadhav
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Jeong
authors.forename: Woo Kyu
authors.initials: WK
authors.lastname: Park
authors.forename: Jong-Hwan
authors.initials: JH
authors.lastname: Song
authors.forename: Sunkyung
authors.initials: S
authors.lastname: Lee
authors.forename: Heeyeong
authors.initials: H
authors.lastname: Cho
mesh_terms: D000818:Animals; D019390:Arrestins / Q000187:drug effects; D016466:CHO Cells; D020013:Calcium Signaling / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D007202:Indicators and Reagents; D009525:Niacin / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011978:Receptors, Nicotinic; D013329:Structure-Activity Relationship; D000071557:beta-Arrestins; D001618:beta-Lactamases / Q000737:chemistry
chemical_list: D019390:Arrestins; D003509:Cyclohexanecarboxylic Acids; C530636:HCAR2 protein, human; D007202:Indicators and Reagents; C549062:MK 6892; D018722:Nicotinic Agonists; D010069:Oxadiazoles; D011720:Pyrazoles; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D000071557:beta-Arrestins; D009525:Niacin; D001618:beta-Lactamases