Target Information

Target General Information

Target ID

T88185 (Former ID: TTDC00317)

Target 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

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Gene Name

HCAR2

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Inborn lipid metabolism error [ICD-11: 5C52]

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.

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BioChemical Class

GPCR rhodopsin

UniProt ID

HCAR2_HUMAN

Sequence

MNRHHLQDHFLEIDKKNCCVFRDDFIVKVLPPVLGLEFIFGLLGNGLALWIFCFHLKSWK
SSRIFLFNLAVADFLLIICLPFLMDNYVRRWDWKFGDIPCRLMLFMLAMNRQGSIIFLTV
VAVDRYFRVVHPHHALNKISNRTAAIISCLLWGITIGLTVHLLKKKMPIQNGGANLCSSF
SICHTFQWHEAMFLLEFFLPLGIILFCSARIIWSLRQRQMDRHAKIKRAITFIMVVAIVF
VICFLPSVVVRIRIFWLLHTSGTQNCEVYRSVDLAFFITLSFTYMNSMLDPVVYYFSSPS
FPNFFSTLINRCLQRKMTGEPDNNRSTSVELTGDPNKTRGAPEALMANSGEPWSPSYLGP
TSP

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3D Structure

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AlphaFold

HIT2.0 ID

T80O6V

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Vitamin B3

Drug Info

Approved

Lipid metabolism disorder

[1]

Clinical Trial Drug(s)

[+] 5 Clinical Trial Drugs

ARI-3037MO

Drug Info

Phase 2

Cardiovascular disease

[2]

GSK-256073

Drug Info

Phase 2

Hyperlipidaemia

[3], [4]

MK-1903

Drug Info

Phase 2

Arteriosclerosis

[5], [6]

SCH-900271

Drug Info

Phase 2

Ischemic stroke

[7], [8]

NIA-114

Drug Info

Clinical trial

Plaque psoriasis

[9]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

INCB19602

Drug Info

Discontinued in Phase 2

Type-2 diabetes

[10]

Mode of Action

[+] 5 Modes of Action

Agonist

[+] 16 Agonist drugs

Vitamin B3

Drug Info

[1]

ARI-3037MO

Drug Info

[2], [11]

GSK-256073

Drug Info

[4], [8]

MK-1903

Drug Info

[8], [13]

NIA-114

Drug Info

[9]

(+)-5-(5-bromothiophen-3-yl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid

Drug Info

[15]

3-pyridine-acetic acid

Drug Info

[20]

5-methyl nicotinic acid

Drug Info

[20]

beta-D-hydroxybutyric acid

Drug Info

[15]

cinnamic acid

Drug Info

[21]

MK-6892

Drug Info

[8]

monomethylfumarate

Drug Info

[22]

PMID19309152C2g

Drug Info

[24]

PMID20363624C(+)17a

Drug Info

[25]

PMID20615702C8f

Drug Info

[12]

PMID21185185C21

Drug Info

[26]

Inhibitor

[+] 18 Inhibitor drugs

MK-0354

Drug Info

[12]

1H-Pyrazole-3-carboxylic acid

Drug Info

[16]

2-(2-(4-tert-butylphenoxy)acetamido)benzoic acid

Drug Info

[17]

2-(3-(naphthalen-2-yl)propanamido)benzoic acid

Drug Info

[17]

2-(3-biphenyl-4-yl-propionylamino)-benzoic acid

Drug Info

[18]

2-(4-phenylbutyl)pyrido[2,3-d]pyrimidin-4(3H)-one

Drug Info

[19]

2-(6-phenylhexyl)pyrido[2,3-d]pyrimidin-4(3H)-one

Drug Info

[19]

2-(cinnamyloxy)pyrido[2,3-d]pyrimidin-4(3H)-one

Drug Info

[19]

4,5,6,7-Tetrahydro-1H-indazole-3-carboxylic acid

Drug Info

[16]

5-(3-Chloro-benzyl)-1H-pyrazole-3-carboxylic acid

Drug Info

[16]

5-(3-Phenyl-propyl)-1H-pyrazole-3-carboxylic acid

Drug Info

[16]

5-(4-Chloro-benzyl)-1H-pyrazole-3-carboxylic acid

Drug Info

[16]

5-Benzyl-1H-pyrazole-3-carboxylic acid

Drug Info

[16]

5-Butyl-1H-pyrazole-3-carboxylic acid

Drug Info

[16]

5-Isopropyl-1H-pyrazole-3-carboxylic acid

Drug Info

[16]

5-Phenethyl-1H-pyrazole-3-carboxylic acid

Drug Info

[16]

5-Propyl-1H-pyrazole-3-carboxylic acid

Drug Info

[16]

ISONICOTINIC ACID

Drug Info

[16]

Modulator

[+] 2 Modulator drugs

SCH-900271

Drug Info

[8]

INCB19602

Drug Info

[14]

Modulator (allosteric modulator)

[+] 2 Modulator (allosteric modulator) drugs

PMID18752940C9n

Drug Info

[23]

PMID22420767C42

Drug Info

[27]

Binder

[+] 1 Binder drugs

Sazetidine-A

Drug Info

[8]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Human Similarity Proteins Human Pathway Affiliation

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Human Similarity Proteins

Human Pathway Affiliation

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Olfactory receptor 4A16 (OR4A16)	PF13853	29.268 (48/164)	1.48E-04

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
cAMP signaling pathway	hsa04024	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 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.

REF 2

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 3

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8470).

REF 4

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.

REF 5

REF 6

ClinicalTrials.gov (NCT00847197) A Study to Evaluate MK1903 in Patients With Dyslipidemia (MK1903-004). U.S. National Institutes of Health.

REF 7

REF 8

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.

REF 9

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 10

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027843)

REF 11

2011 Pipeline of Arisaph Pharmaceuticals.

REF 12

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.

REF 13

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.

REF 14

DOI: 10.1038/scibx.2010.313

REF 15

(D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J Biol Chem. 2005 Jul 22;280(29):26649-52.

REF 16

Pyrazole derivatives as partial agonists for the nicotinic acid receptor. J Med Chem. 2003 Aug 28;46(18):3945-51.

REF 17

Molecular modeling aided design of nicotinic acid receptor GPR109A agonists. Bioorg Med Chem Lett. 2008 Sep 15;18(18):4963-7.

REF 18

Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor. J Med Chem. 2007 Dec 13;50(25):6303-6.

REF 19

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.

REF 20

Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem. 2003 Mar 14;278(11):9869-74.

REF 21

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.

REF 22

The psoriasis drug monomethylfumarate is a potent nicotinic acid receptor agonist. Biochem Biophys Res Commun. 2008 Oct 31;375(4):562-5.

REF 23

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.

REF 24

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.

REF 25

Potent tricyclic pyrazole tetrazole agonists of the nicotinic acid receptor (GPR109a). Bioorg Med Chem Lett. 2010 May 1;20(9):2797-800.

REF 26

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.

REF 27

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.

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