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Discovery of 4-(phenyl)thio-1H-pyrazole derivatives as agonists of GPR109A, a high affinity niacin receptor.
Arch Pharm Res. 2015 Jun; 38(6):1019-32.AP

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+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25599616

Citation

Kim, Hyeon Young, et al. "Discovery of 4-(phenyl)thio-1H-pyrazole Derivatives as Agonists of GPR109A, a High Affinity Niacin Receptor." Archives of Pharmacal Research, vol. 38, no. 6, 2015, pp. 1019-32.
Kim HY, Jadhav VB, Jeong DY, et al. Discovery of 4-(phenyl)thio-1H-pyrazole derivatives as agonists of GPR109A, a high affinity niacin receptor. Arch Pharm Res. 2015;38(6):1019-32.
Kim, H. Y., Jadhav, V. B., Jeong, D. Y., Park, W. K., Song, J. H., Lee, S., & Cho, H. (2015). Discovery of 4-(phenyl)thio-1H-pyrazole derivatives as agonists of GPR109A, a high affinity niacin receptor. Archives of Pharmacal Research, 38(6), 1019-32. https://doi.org/10.1007/s12272-015-0560-4
Kim HY, et al. Discovery of 4-(phenyl)thio-1H-pyrazole Derivatives as Agonists of GPR109A, a High Affinity Niacin Receptor. Arch Pharm Res. 2015;38(6):1019-32. PubMed PMID: 25599616.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of 4-(phenyl)thio-1H-pyrazole derivatives as agonists of GPR109A, a high affinity niacin receptor. AU - Kim,Hyeon Young, AU - Jadhav,Vithal B, AU - Jeong,Dae Young, AU - Park,Woo Kyu, AU - Song,Jong-Hwan, AU - Lee,Sunkyung, AU - Cho,Heeyeong, Y1 - 2015/01/20/ PY - 2014/09/29/received PY - 2015/01/08/accepted PY - 2015/1/21/entrez PY - 2015/1/21/pubmed PY - 2016/3/10/medline SP - 1019 EP - 32 JF - Archives of pharmacal research JO - Arch Pharm Res VL - 38 IS - 6 N2 - 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. SN - 0253-6269 UR - https://www.unboundmedicine.com/medline/citation/25599616/Discovery_of_4__phenyl_thio_1H_pyrazole_derivatives_as_agonists_of_GPR109A_a_high_affinity_niacin_receptor_ L2 - https://dx.doi.org/10.1007/s12272-015-0560-4 DB - PRIME DP - Unbound Medicine ER -