NIACIN

General Information

Mainterm	NIACIN
Doc Type	ASP
CAS Reg.No.(or other ID)	59-67-6
Regnum	139.122 101.9 107.100 137.165 137.235 137.260 137.305 137.350 139.115 139.155 136.115 137.180 139.117 184.1530

From www.fda.gov

Computed Descriptors

Download SDF

2D Structure
CID	938
IUPAC Name	pyridine-3-carboxylic acid
InChI	InChI=1S/C6H5NO2/c8-6(9)5-2-1-3-7-4-5/h1-4H,(H,8,9)
InChI Key	PVNIIMVLHYAWGP-UHFFFAOYSA-N
Canonical SMILES	C1=CC(=CN=C1)C(=O)O
Molecular Formula	C6H5NO2
Wikipedia	nicotinate

From Pubchem

Computed Properties

Property Name	Property Value
Molecular Weight	123.111
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	3
Rotatable Bond Count	1
Complexity	114.0
CACTVS Substructure Key Fingerprint	A A A D c Y B i M A A A A A A A A A A A A A A A A A A A A A A A A A A s A A A A A A A A A A A B g A A A H g A A C A A A D A D B m g Q 8 i J I I E g C o A j D 3 T A C C g C A 1 A i A I 2 C E 4 b N g I J v r A l Z G E c Y h m w A H I 2 c a Y E Q I M A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A = =
Topological Polar Surface Area	50.2
Monoisotopic Mass	123.032
Exact Mass	123.032
Compound Is Canonicalized	True
Formal Charge	0
Heavy Atom Count	9
Defined Atom Stereocenter Count	0
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Isotope Atom Count	0
Covalently-Bonded Unit Count	1

From Pubchem

Food Additives Biosynthesis/Degradation

ADMET Predicted Profile --- Classification

Model	Result	Probability
Absorption
Blood-Brain Barrier	BBB+	0.9648
Human Intestinal Absorption	HIA+	0.9672
Caco-2 Permeability	Caco2+	0.8701
P-glycoprotein Substrate	Non-substrate	0.8683
P-glycoprotein Inhibitor	Non-inhibitor	0.9935
P-glycoprotein Inhibitor	Non-inhibitor	1.0000
Renal Organic Cation Transporter	Non-inhibitor	0.8938
Distribution
Subcellular localization	Mitochondria	0.8256
Metabolism
CYP450 2C9 Substrate	Non-substrate	0.8246
CYP450 2D6 Substrate	Non-substrate	0.9231
CYP450 3A4 Substrate	Non-substrate	0.8381
CYP450 1A2 Inhibitor	Non-inhibitor	0.9045
CYP450 2C9 Inhibitor	Non-inhibitor	0.9070
CYP450 2D6 Inhibitor	Non-inhibitor	0.9230
CYP450 2C19 Inhibitor	Non-inhibitor	0.9400
CYP450 3A4 Inhibitor	Non-inhibitor	0.9120
CYP Inhibitory Promiscuity	Low CYP Inhibitory Promiscuity	0.9875
Excretion
Toxicity
Human Ether-a-go-go-Related Gene Inhibition	Weak inhibitor	0.9557
Human Ether-a-go-go-Related Gene Inhibition	Non-inhibitor	0.9829
AMES Toxicity	Non AMES toxic	0.9939
Carcinogens	Non-carcinogens	0.8566
Fish Toxicity	Low FHMT	0.6230
Tetrahymena Pyriformis Toxicity	Low TPT	0.7721
Honey Bee Toxicity	Low HBT	0.5000
Biodegradation	Ready biodegradable	0.9437
Acute Oral Toxicity	IV	0.6559
Carcinogenicity (Three-class)	Non-required	0.6790

From admetSAR

ADMET Predicted Profile --- Regression

Model	Value	Unit
Absorption
Aqueous solubility	-0.7773	LogS
Caco-2 Permeability	1.7239	LogPapp, cm/s
Distribution
Metabolism
Excretion
Toxicity
Rat Acute Toxicity	1.2760	LD50, mol/kg
Fish Toxicity	2.4968	pLC50, mg/L
Tetrahymena Pyriformis Toxicity	-0.7904	pIGC50, ug/L

From admetSAR

Toxicity Profile

Route of Exposure	Oral ; Intramuscular . Both nicotinic acid and nicotinamide are efficiently absorbed from the stomach and small intestine.
Mechanism of Toxicity	Niacin binds to Nicotinate D-ribonucleotide phyrophsopate phosphoribosyltransferase, Nicotinic acid phosphoribosyltransferase, Nicotinate N-methyltransferase and the Niacin receptor. Niacin is the precursor to nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are vital cofactors for dozens of enzymes. The mechanism by which niacin exerts its lipid lowering effects is not entirely understood, but may involve several actions, including a decrease in esterification of hepatic triglycerides. Niacin treatment also decreases the serum levels of apolipoprotein B-100 (apo B), the major protein component of the VLDL (very low-density lipoprotein) and LDL fractions.
Metabolism	Niacin is rapidly metabolized and undergoes extensive first-pass metabolism in the liver. The drug is converted to several metabolites, including nicotinuric acid (NUA), nicotinamide, and nicotinamide adenine dinucleotide (NAD). At doses used to treat hyperlipoproteinemia, the principal metabolic pathways appear to be saturable, and niacin is thought to exhibit nonlinear, dose-dependent pharmacokinetics. Half Life: 20-45 minutes.
Toxicity Values	LD50: 7000 mg/kg (Oral, Rat) LD50: 730 mg/kg (Intraperitoneal, Rat) LD50: 3500 mg/kg (Subcutaneous, Mouse)
Lethal Dose	None
Carcinogenicity (IARC Classification)	No indication of carcinogenicity to humans (not listed by IARC).
Minimum Risk Level	None
Health Effects	Niacin at extremely high doses can have life-threatening acute toxic reactions. Extremely high doses of niacin can also cause niacin maculopathy, a thickening of the macula and retina which leads to blurred vision and blindness. This maculopathy is reversible after stopping niacin intake. Side effects of hyperglycemia, cardiac arrhythmias and birth defects have also been reported. (A729)
Treatment	Supportive measures should be undertaken in the event of an overdose.
Reference	Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.[17139284 ] Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34.[17016423 ] Nathanson JA: Caffeine and related methylxanthines: possible naturally occurring pesticides. Science. 1984 Oct 12;226(4671):184-7.[6207592 ] Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, Offermanns S: PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med. 2003 Mar;9(3):352-5. Epub 2003 Feb 3.[12563315 ] Taggart AK, Kero J, Gan X, Cai TQ, Cheng K, Ippolito M, Ren N, Kaplan R, Wu K, Wu TJ, Jin L, Liaw C, Chen R, Richman J, Connolly D, Offermanns S, Wright SD, Waters MG: (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J Biol Chem. 2005 Jul 22;280(29):26649-52. Epub 2005 Jun 1.[15929991 ] Zhang Y, Schmidt RJ, Foxworthy P, Emkey R, Oler JK, Large TH, Wang H, Su EW, Mosior MK, Eacho PI, Cao G: Niacin mediates lipolysis in adipose tissue through its G-protein coupled receptor HM74A. Biochem Biophys Res Commun. 2005 Aug 26;334(2):729-32.[16018973 ] Tunaru S, Lattig J, Kero J, Krause G, Offermanns S: Characterization of determinants of ligand binding to the nicotinic acid receptor GPR109A (HM74A/PUMA-G). Mol Pharmacol. 2005 Nov;68(5):1271-80. Epub 2005 Aug 11.[16099840 ] Benyo Z, Gille A, Kero J, Csiky M, Suchankova MC, Nusing RM, Moers A, Pfeffer K, Offermanns S: GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing. J Clin Invest. 2005 Dec;115(12):3634-40.[16322797 ] Fukuwatari T, Morikawa Y, Hayakawa F, Sugimoto E, Shibata K: Influence of adenine-induced renal failure on tryptophan-niacin metabolism in rats. Biosci Biotechnol Biochem. 2001 Oct;65(10):2154-61.[11758903 ] Shin DH, Oganesyan N, Jancarik J, Yokota H, Kim R, Kim SH: Crystal structure of a nicotinate phosphoribosyltransferase from Thermoplasma acidophilum. J Biol Chem. 2005 May 6;280(18):18326-35. Epub 2005 Mar 6.[15753098 ] Zheng XQ, Hayashibe E, Ashihara H: Changes in trigonelline (N-methylnicotinic acid) content and nicotinic acid metabolism during germination of mungbean (Phaseolus aureus) seeds. J Exp Bot. 2005 Jun;56(416):1615-23. Epub 2005 Apr 18.[15837705 ] Wise A, Foord SM, Fraser NJ, Barnes AA, Elshourbagy N, Eilert M, Ignar DM, Murdock PR, Steplewski K, Green A, Brown AJ, Dowell SJ, Szekeres PG, Hassall DG, Marshall FH, Wilson S, Pike NB: Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem. 2003 Mar 14;278(11):9869-74. Epub 2003 Jan 9.[12522134 ] Soga T, Kamohara M, Takasaki J, Matsumoto S, Saito T, Ohishi T, Hiyama H, Matsuo A, Matsushime H, Furuichi K: Molecular identification of nicotinic acid receptor. Biochem Biophys Res Commun. 2003 Mar 28;303(1):364-9.[12646212 ] Zellner C, Pullinger CR, Aouizerat BE, Frost PH, Kwok PY, Malloy MJ, Kane JP: Variations in human HM74 (GPR109B) and HM74A (GPR109A) niacin receptors. Hum Mutat. 2005 Jan;25(1):18-21.[15580557 ] Dastur DK, Santhadevi N, Quadros EV, Avari FC, Wadia NH, Desai MN, Bharucha EP: The B-vitamins in malnutrition with alcoholism. A model of intervitamin relationships. Br J Nutr. 1976 Sep;36(2):143-59.[182198 ] Gopal E, Fei YJ, Miyauchi S, Zhuang L, Prasad PD, Ganapathy V: Sodium-coupled and electrogenic transport of B-complex vitamin nicotinic acid by slc5a8, a member of the Na/glucose co-transporter gene family. Biochem J. 2005 May 15;388(Pt 1):309-16.[15651982 ] Salvi A, Carrupt PA, Mayer JM, Testa B: Esterase-like activity of human serum albumin toward prodrug esters of nicotinic acid. Drug Metab Dispos. 1997 Apr;25(4):395-8.[9107536 ] Hertle H, Kiese M, Renner G: Absorption in rats, dogs, pigs, and humans of nicotinic acid after oral administration of phosphatidyl inositol pentanicotinate hydrochloride (PIN). Arzneimittelforschung. 1979;29(1):114-6.[582105 ] Zarzycki PK, Kowalski P, Nowakowska J, Lamparczyk H: High-performance liquid chromatographic and capillary electrophoretic determination of free nicotinic acid in human plasma and separation of its metabolites by capillary electrophoresis. J Chromatogr A. 1995 Aug 11;709(1):203-8.[7581845 ] Hengen N, Seiberth V, Hengen M: High-performance liquid-chromatographic determination of free nicotinic acid and its metabolite, nicotinuric acid, in plasma and urine. Clin Chem. 1978 Oct;24(10):1740-3.[699281 ] Santos RD: [Pharmacology of niacin or nicotinic acid]. Arq Bras Cardiol. 2005 Oct;85 Suppl 5:17-9. Epub 2006 Jan 2.[16400392 ] Mrochek JE, Jolley RL, Young DS, Turner WJ: Metabolic response of humans to ingestion of nicotinic acid and nicotinamide. Clin Chem. 1976 Nov;22(11):1821-7.[135660 ] Pike NB: Flushing out the role of GPR109A (HM74A) in the clinical efficacy of nicotinic acid. J Clin Invest. 2005 Dec;115(12):3400-3.[16322787 ] Kobayashi M, Shimizu S: [Nicotinic acid and nicotinamide]. Nihon Rinsho. 1999 Oct;57(10):2211-7.[10540864 ] Sutherland WH, Larking PW, Nye ER: Modification of nicotinic acid and prostaglandin E1 antilipolytic action in vitro. Atherosclerosis. 1976 Oct;25(1):45-53.[186078 ] Stratford MR, Dennis MF, Hoskin P, Phillips H, Hodgkiss RJ, Rojas A: Nicotinamide pharmacokinetics in humans: effect of gastric acid inhibition, comparison of rectal vs oral administration and the use of saliva for drug monitoring. Br J Cancer. 1996 Jul;74(1):16-21.[8679452 ] Angelin B, Einarsson K, Leijd B: Biliary lipid composition during treatment with different hypolipidaemic drugs. Eur J Clin Invest. 1979 Jun;9(3):185-90.[113218 ] Patterson MC, Di Bisceglie AM, Higgins JJ, Abel RB, Schiffmann R, Parker CC, Argoff CE, Grewal RP, Yu K, Pentchev PG, et al.: The effect of cholesterol-lowering agents on hepatic and plasma cholesterol in Niemann-Pick disease type C. Neurology. 1993 Jan;43(1):61-4.[8423912 ] Muller B, Kasper M, Surber C, Imanidis G: Permeation, metabolism and site of action concentration of nicotinic acid derivatives in human skin. Correlation with topical pharmacological effect. Eur J Pharm Sci. 2003 Oct;20(2):181-95.[14550884 ] Chekalina SI, Guseva LI, Bardyechev MS: [Use of nicotinic acid and midocalm for correcting blood coagulation in patients with radiation edema of the extremities]. Med Radiol (Mosk). 1985 Aug;30(8):28-30.[4033386 ]

From T3DB

Taxonomic Classification

Kingdom	Organic compounds
Superclass	Organoheterocyclic compounds
Class	Pyridines and derivatives
Subclass	Pyridinecarboxylic acids and derivatives
Intermediate Tree Nodes	Not available
Direct Parent	Pyridinecarboxylic acids
Alternative Parents	Organopnictogen compounds Organonitrogen compounds Monocarboxylic acids and derivatives Hydrocarbon derivatives Organic oxides Organooxygen compounds Heteroaromatic compounds Carboxylic acids Azacyclic compounds
Molecular Framework	Aromatic heteromonocyclic compounds
Substituents	Pyridine carboxylic acid - Heteroaromatic compound - Azacycle - Monocarboxylic acid or derivatives - Carboxylic acid - Carboxylic acid derivative - Organic nitrogen compound - Organic oxygen compound - Organopnictogen compound - Organic oxide - Hydrocarbon derivative - Organooxygen compound - Organonitrogen compound - Aromatic heteromonocyclic compound
Description	This compound belongs to the class of organic compounds known as pyridinecarboxylic acids. These are compounds containing a pyridine ring bearing a carboxylic acid group.

From ClassyFire

Targets

Target Details

Hydroxycarboxylic acid receptor 2

General Function:: Nicotinic acid receptor activity
Specific 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.
Gene Name:: HCAR2
Uniprot ID:: Q8TDS4
Molecular Weight:: 41849.08 Da

References

van Veldhoven JP, Blad CC, Artsen CM, Klopman C, Wolfram DR, Abdelkadir MJ, Lane JR, Brussee J, Ijzerman AP: Structure-activity relationships of trans-substituted-propenoic acid derivatives on the nicotinic acid receptor HCA2 (GPR109A). Bioorg Med Chem Lett. 2011 May 1;21(9):2736-9. doi: 10.1016/j.bmcl.2010.11.091. Epub 2010 Nov 25. [21167710 ]

Target Details

Hydroxycarboxylic acid receptor 3

General Function:: G-protein coupled receptor activity
Specific Function:: Receptor for 3-OH-octanoid acid mediates a negative feedback regulation of adipocyte lipolysis to counteract prolipolytic influences under conditions of physiological or pathological increases in beta-oxidation rates. Acts as a low affinity receptor for nicotinic acid. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet.
Gene Name:: HCAR3
Uniprot ID:: P49019
Molecular Weight:: 44477.93 Da

References

Mahboubi K, Witman-Jones T, Adamus JE, Letsinger JT, Whitehouse D, Moorman AR, Sawicki D, Bergenhem N, Ross SA: Triglyceride modulation by acifran analogs: activity towards the niacin high and low affinity G protein-coupled receptors HM74A and HM74. Biochem Biophys Res Commun. 2006 Feb 10;340(2):482-90. Epub 2005 Dec 19. [16389067 ]

Target Details

Nicotinate-nucleotide pyrophosphorylase [carboxylating]

General Function:: Protein homodimerization activity
Specific Function:: Involved in the catabolism of quinolinic acid (QA).
Gene Name:: QPRT
Uniprot ID:: Q15274
Molecular Weight:: 30845.31 Da

References

Zheng XQ, Hayashibe E, Ashihara H: Changes in trigonelline (N-methylnicotinic acid) content and nicotinic acid metabolism during germination of mungbean (Phaseolus aureus) seeds. J Exp Bot. 2005 Jun;56(416):1615-23. Epub 2005 Apr 18. [15837705 ]

Target Details

Nicotinamide N-methyltransferase

General Function:: Nicotinamide n-methyltransferase activity
Specific Function:: Catalyzes the N-methylation of nicotinamide and other pyridines to form pyridinium ions. This activity is important for biotransformation of many drugs and xenobiotic compounds.
Gene Name:: NNMT
Uniprot ID:: P40261
Molecular Weight:: 29573.705 Da

References

Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]

From T3DB