Target Validation Information
Target ID T88185
Target Name Nicotinic acid receptor
Target Type
Successful
Drug Potency against Target INCB19602 Drug Info IC50 = 1.2~13 nM [552956]
2-(4-phenylbutyl)pyrido[2,3-d]pyrimidin-4(3H)-one Drug Info IC50 = 4400 nM [531113]
2-(6-phenylhexyl)pyrido[2,3-d]pyrimidin-4(3H)-one Drug Info IC50 = 19000 nM [531113]
5-Propyl-1H-pyrazole-3-carboxylic acid Drug Info Ki = 143 nM [526698]
2-(3-(naphthalen-2-yl)propanamido)benzoic acid Drug Info IC50 = 140 nM [529664]
2-(3-biphenyl-4-yl-propionylamino)-benzoic acid Drug Info IC50 = 94 nM [529144]
4,5,6,7-Tetrahydro-1H-indazole-3-carboxylic acid Drug Info Ki = 3540 nM [526698]
5-Phenethyl-1H-pyrazole-3-carboxylic acid Drug Info Ki = 1570 nM [526698]
ISONICOTINIC ACID Drug Info Ki = 33 nM [526698]
5-(4-Chloro-benzyl)-1H-pyrazole-3-carboxylic acid Drug Info Ki = 3610 nM [526698]
5-Benzyl-1H-pyrazole-3-carboxylic acid Drug Info Ki = 1250 nM [526698]
1H-Pyrazole-3-carboxylic acid Drug Info Ki = 594 nM [526698]
5-Butyl-1H-pyrazole-3-carboxylic acid Drug Info Ki = 72 nM [526698]
5-Isopropyl-1H-pyrazole-3-carboxylic acid Drug Info Ki = 683 nM [526698]
5-(3-Chloro-benzyl)-1H-pyrazole-3-carboxylic acid Drug Info Ki = 504 nM [526698]
2-(cinnamyloxy)pyrido[2,3-d]pyrimidin-4(3H)-one Drug Info IC50 = 370 nM [531113]
5-(3-Phenyl-propyl)-1H-pyrazole-3-carboxylic acid Drug Info Ki = 6300 nM [526698]
MK-0354 Drug Info IC50 = 1200 nM [531020]
2-(2-(4-tert-butylphenoxy)acetamido)benzoic acid Drug Info IC50 = 1200 nM [529664]
The Effect of Target Knockout, Knockdown or Genetic Variations The niacin receptor GPR109A is a G(i)-protein-coupled receptor which mediates the effects of niacin on inhibiting intracellular triglyceride lipolysis in adipocytes. However, the role of GPR109A in mediating the effects of niacin on high density lipoprotein (HDL) metabolism is unclear. We found niacin has no effect on HDL-C in GPR109A knockout mice. Furthermore, niacin lowered intracellular cAMP in primary hepatocytes mediated by GPR109A. We used an adeno-associated viral (AAV) serotype 8 vector encoding GPR109A under the control of the hepatic-specific thyroxine-bindingglobulin promoter to specifically overexpress GPR109A in mouse liver. Plasma HDL-C, hepatic ABCA1 and the HDL cholesterol production rate were significantly reduced in mice overexpressing GPR109A. Overexpression of GPR109A reduced primary hepatocyte free cholesterol efflux to apoA-I; conversely, GPR109A deficient hepatocytes had increased ABCA1-mediated cholesterol efflux. These data support the concept that the HDL-C lowering effect of niacin in wild-type mice is mediated through stimulation of GPR109A in hepatocytes; such an effect then leads to reduced hepatocyte ABCA1 expression and activity, decreased cholesterol efflux to nascent apoA-I, and reduced HDL-C levels. These results indicate that niacin-mediated activation of GP109A in liver lowers ABCA1 expression leading to reduced hepatic cholesterol efflux to HDL [552956]
References
Ref 552956Novel patent publications on high-affinity nicotinic acid receptor agonists. Expert Opin Ther Pat. 2009 Jul;19(7):957-67. doi: 10.1517/13543770902991526.
Ref 531113Bioorg Med Chem Lett. 2010 Sep 15;20(18):5426-30. Epub 2010 Jul 29.Pyrido pyrimidinones as selective agonists of the high affinity niacin receptor GPR109A: optimization of in vitro activity.
Ref 531113Bioorg Med Chem Lett. 2010 Sep 15;20(18):5426-30. Epub 2010 Jul 29.Pyrido pyrimidinones as selective agonists of the high affinity niacin receptor GPR109A: optimization of in vitro activity.
Ref 526698J Med Chem. 2003 Aug 28;46(18):3945-51.Pyrazole derivatives as partial agonists for the nicotinic acid receptor.
Ref 529664Bioorg Med Chem Lett. 2008 Sep 15;18(18):4963-7. Epub 2008 Aug 14.Molecular modeling aided design of nicotinic acid receptor GPR109A agonists.
Ref 529144J Med Chem. 2007 Dec 13;50(25):6303-6. Epub 2007 Nov 10.Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor.
Ref 526698J Med Chem. 2003 Aug 28;46(18):3945-51.Pyrazole derivatives as partial agonists for the nicotinic acid receptor.
Ref 526698J Med Chem. 2003 Aug 28;46(18):3945-51.Pyrazole derivatives as partial agonists for the nicotinic acid receptor.
Ref 526698J Med Chem. 2003 Aug 28;46(18):3945-51.Pyrazole derivatives as partial agonists for the nicotinic acid receptor.
Ref 526698J Med Chem. 2003 Aug 28;46(18):3945-51.Pyrazole derivatives as partial agonists for the nicotinic acid receptor.
Ref 526698J Med Chem. 2003 Aug 28;46(18):3945-51.Pyrazole derivatives as partial agonists for the nicotinic acid receptor.
Ref 526698J Med Chem. 2003 Aug 28;46(18):3945-51.Pyrazole derivatives as partial agonists for the nicotinic acid receptor.
Ref 526698J Med Chem. 2003 Aug 28;46(18):3945-51.Pyrazole derivatives as partial agonists for the nicotinic acid receptor.
Ref 526698J Med Chem. 2003 Aug 28;46(18):3945-51.Pyrazole derivatives as partial agonists for the nicotinic acid receptor.
Ref 526698J Med Chem. 2003 Aug 28;46(18):3945-51.Pyrazole derivatives as partial agonists for the nicotinic acid receptor.
Ref 531113Bioorg Med Chem Lett. 2010 Sep 15;20(18):5426-30. Epub 2010 Jul 29.Pyrido pyrimidinones as selective agonists of the high affinity niacin receptor GPR109A: optimization of in vitro activity.
Ref 526698J Med Chem. 2003 Aug 28;46(18):3945-51.Pyrazole derivatives as partial agonists for the nicotinic acid receptor.
Ref 531020Bioorg Med Chem Lett. 2010 Aug 1;20(15):4472-4. Epub 2010 Jun 10.GPR109a agonists. Part 2: pyrazole-acids as agonists of the human orphan G-protein coupled receptor GPR109a.
Ref 529664Bioorg Med Chem Lett. 2008 Sep 15;18(18):4963-7. Epub 2008 Aug 14.Molecular modeling aided design of nicotinic acid receptor GPR109A agonists.

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