General Information of Drug Therapeutic Target (DTT) (ID: TTWNV8U)

DTT Name Nicotinic acid receptor (HCAR2)
Synonyms Niacin receptor 1; NIACR1; Hydroxycarboxylic acid receptor 2; HM74A; HCA2; GPR109A; G-protein coupled receptor HM74A; G-protein coupled receptor 109A
Gene Name HCAR2
DTT Type
Successful target
[1]
BioChemical Class
GPCR rhodopsin
UniProt ID
HCAR2_HUMAN
TTD ID
T88185
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Sequence
MNRHHLQDHFLEIDKKNCCVFRDDFIVKVLPPVLGLEFIFGLLGNGLALWIFCFHLKSWK
SSRIFLFNLAVADFLLIICLPFLMDNYVRRWDWKFGDIPCRLMLFMLAMNRQGSIIFLTV
VAVDRYFRVVHPHHALNKISNRTAAIISCLLWGITIGLTVHLLKKKMPIQNGGANLCSSF
SICHTFQWHEAMFLLEFFLPLGIILFCSARIIWSLRQRQMDRHAKIKRAITFIMVVAIVF
VICFLPSVVVRIRIFWLLHTSGTQNCEVYRSVDLAFFITLSFTYMNSMLDPVVYYFSSPS
FPNFFSTLINRCLQRKMTGEPDNNRSTSVELTGDPNKTRGAPEALMANSGEPWSPSYLGP
TSP
Function
Acts as a high affinity receptor for both nicotinic acid (also known as niacin) and (D)-beta-hydroxybutyrate and mediates increased adiponectin secretion and decreased lipolysis through G(i)-protein-mediated inhibition of adenylyl cyclase. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet. Mediates nicotinic acid-induced apoptosis in mature neutrophils. Receptor activation by nicotinic acid results in reduced cAMP levels which may affect activity of cAMP-dependent protein kinase A and phosphorylation of target proteins, leading to neutrophil apoptosis. The rank order of potency for the displacement of nicotinic acid binding is 5-methyl pyrazole-3-carboxylic acid = pyridine-3-acetic acid > acifran > 5-methyl nicotinic acid = acipimox >> nicotinuric acid = nicotinamide.
KEGG Pathway
cAMP signaling pathway (hsa04024 )
Reactome Pathway
G alpha (i) signalling events (R-HSA-418594 )
Class A/1 (Rhodopsin-like receptors) (R-HSA-373076 )

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
1 Approved Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
Vitamin B3 DMQVRZH Chronic renal failure GB61.Z Approved [1]
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6 Clinical Trial Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
ARI-3037MO DM9LNXS Cardiovascular disease BA00-BE2Z Phase 2 [2]
GSK-256073 DMMAIY2 Hyperlipidaemia 5C80 Phase 2 [3]
MK-0354 DMWFTRJ N. A. N. A. Phase 2 [4]
MK-1903 DMVJB09 Arteriosclerosis BD40 Phase 2 [5]
SCH-900271 DMBJY1Z Ischemic stroke 8B11.5Z Phase 2 [6]
NIA-114 DM3ADQW Plaque psoriasis EA90.0 Clinical trial [7]
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⏷ Show the Full List of 6 Clinical Trial Drug(s)
1 Discontinued Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
INCB19602 DMRHZBD Type-2 diabetes 5A11 Discontinued in Phase 2 [8]
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31 Investigative Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
(+)-5-(5-bromothiophen-3-yl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid DM2CHX8 Discovery agent N.A. Investigative [9]
1H-Pyrazole-3-carboxylic acid DM4V6JE Discovery agent N.A. Investigative [10]
2-(2-(4-tert-butylphenoxy)acetamido)benzoic acid DMKT51Z Discovery agent N.A. Investigative [11]
2-(3-(naphthalen-2-yl)propanamido)benzoic acid DMKEY9V Discovery agent N.A. Investigative [11]
2-(3-biphenyl-4-yl-propionylamino)-benzoic acid DMY60K3 Discovery agent N.A. Investigative [12]
2-(4-phenylbutyl)pyrido[2,3-d]pyrimidin-4(3H)-one DMNJAV1 Discovery agent N.A. Investigative [13]
2-(6-phenylhexyl)pyrido[2,3-d]pyrimidin-4(3H)-one DMR3Z1D Discovery agent N.A. Investigative [13]
2-(cinnamyloxy)pyrido[2,3-d]pyrimidin-4(3H)-one DM0PA6I Discovery agent N.A. Investigative [13]
3-pyridine-acetic acid DMAGXMJ Discovery agent N.A. Investigative [14]
4,5,6,7-Tetrahydro-1H-indazole-3-carboxylic acid DMDQL24 Discovery agent N.A. Investigative [10]
5-(3-Chloro-benzyl)-1H-pyrazole-3-carboxylic acid DMCR9KX Discovery agent N.A. Investigative [10]
5-(3-Phenyl-propyl)-1H-pyrazole-3-carboxylic acid DMPCFA6 Discovery agent N.A. Investigative [10]
5-(4-Chloro-benzyl)-1H-pyrazole-3-carboxylic acid DMDCNZE Discovery agent N.A. Investigative [10]
5-Benzyl-1H-pyrazole-3-carboxylic acid DMJVGUZ Discovery agent N.A. Investigative [10]
5-Butyl-1H-pyrazole-3-carboxylic acid DMXKQFM Discovery agent N.A. Investigative [10]
5-Isopropyl-1H-pyrazole-3-carboxylic acid DME6BX5 Discovery agent N.A. Investigative [10]
5-methyl nicotinic acid DM0AIOW Discovery agent N.A. Investigative [14]
5-Phenethyl-1H-pyrazole-3-carboxylic acid DMZKJF8 Discovery agent N.A. Investigative [10]
5-Propyl-1H-pyrazole-3-carboxylic acid DMSPVXM Discovery agent N.A. Investigative [10]
beta-D-hydroxybutyric acid DMNE4C6 Discovery agent N.A. Investigative [9]
cinnamic acid DM340FH Discovery agent N.A. Investigative [15]
ISONICOTINIC ACID DMUVAIF Discovery agent N.A. Investigative [10]
MK-6892 DMR9C4Q Arteriosclerosis BD40 Investigative [6]
monomethylfumarate DMU4JWM Discovery agent N.A. Investigative [16]
PMID18752940C9n DMPZSGV Discovery agent N.A. Investigative [17]
PMID19309152C2g DMTASYN Discovery agent N.A. Investigative [18]
PMID20363624C(+)17a DMCAXNU Discovery agent N.A. Investigative [19]
PMID20615702C8f DMN2HXL Discovery agent N.A. Investigative [4]
PMID21185185C21 DM1BQY3 Discovery agent N.A. Investigative [20]
PMID22420767C42 DM123TU Discovery agent N.A. Investigative [21]
Sazetidine-A DM68JI5 Major depressive disorder 6A70.3 Investigative [6]
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⏷ Show the Full List of 31 Investigative Drug(s)

References

1 Hakozaki T, Minwalla L, Zhuang J, Chhoa M, Matsubara A, Miyamoto K, Greatens A, Hillebrand GG, Bissett DL, Boissy RE: The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer. Br J Dermatol. 2002 Jul;147(1):20-31.
2 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
3 GSK256073, a selective agonist of G-protein coupled receptor 109A (GPR109A) reduces serum glucose in subjects with type 2 diabetes mellitus. Diabetes Obes Metab. 2013 Nov;15(11):1013-21.
4 GPR109a agonists. Part 2: pyrazole-acids as agonists of the human orphan G-protein coupled receptor GPR109a. Bioorg Med Chem Lett. 2010 Aug 1;20(15):4472-4.
5 Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression. Sci Transl Med. 2012 Aug 22;4(148):148ra115.
6 Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia. ACS Med Chem Lett. 2011 Nov 24;3(1):63-8.
7 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
8 DOI: 10.1038/scibx.2010.313
9 (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J Biol Chem. 2005 Jul 22;280(29):26649-52.
10 Pyrazole derivatives as partial agonists for the nicotinic acid receptor. J Med Chem. 2003 Aug 28;46(18):3945-51.
11 Molecular modeling aided design of nicotinic acid receptor GPR109A agonists. Bioorg Med Chem Lett. 2008 Sep 15;18(18):4963-7.
12 Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor. J Med Chem. 2007 Dec 13;50(25):6303-6.
13 Pyrido pyrimidinones as selective agonists of the high affinity niacin receptor GPR109A: optimization of in vitro activity. Bioorg Med Chem Lett. 2010 Sep 15;20(18):5426-30.
14 Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem. 2003 Mar 14;278(11):9869-74.
15 Phenolic acids suppress adipocyte lipolysis via activation of the nicotinic acid receptor GPR109A (HM74a/PUMA-G). J Lipid Res. 2009 May;50(5):908-14.
16 The psoriasis drug monomethylfumarate is a potent nicotinic acid receptor agonist. Biochem Biophys Res Commun. 2008 Oct 31;375(4):562-5.
17 Discovery of pyrazolopyrimidines as the first class of allosteric agonists for the high affinity nicotinic acid receptor GPR109A. Bioorg Med Chem Lett. 2008 Sep 15;18(18):4948-51.
18 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.
19 Potent tricyclic pyrazole tetrazole agonists of the nicotinic acid receptor (GPR109a). Bioorg Med Chem Lett. 2010 May 1;20(9):2797-800.
20 The discovery of high affinity agonists of GPR109a with reduced serum shift and improved ADME properties. Bioorg Med Chem Lett. 2011 May 1;21(9):2721-4.
21 Novel 3,6,7-substituted pyrazolopyrimidines as positive allosteric modulators for the hydroxycarboxylic acid receptor 2 (GPR109A). J Med Chem. 2012 Apr 12;55(7):3563-7.