Details of the Drug Therapeutic Target (DTT)

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
• 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

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]

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]

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]

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]

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.