Details of the Drug

General Information of Drug (ID: DM5X7VY)

Drug Name

Pyrimethamine

Synonyms

Chloridin; Chloridine; Chloridyn; Darachlor; Daraclor; Darapram; Daraprim; Daraprime; Daraprin; Diaminopyritamin; Erbaprelina; Ethylpyrimidine; Khloridin; Malacid; Malocid; Malocide; Maloprim; Pirimecidan; Pirimetamin; Pirimetamina; Primethamine; Pyremethamine; Pyrimethamin; Pyrimethaminum; Tindurin; Tindurine; Tinduring; Aventis Brand of Pyrimethamine; Glaxo Wellcome Brand of Pyrimethamine; GlaxoSmithKline Brand of Pyrimethamine; M alocid; Pirimetamina [Spanish]; Pyrimethamine Hcl; Wellcome Brand of Pyrimethamine; BW 5063; RP 4753; WR 2978; AZT + Pyrimethamine combination; BW 50-63; Daraprim (TN); EXR-101; Lactoferrin B & Pyrimethamine; Lactoferrin H & Pyrimethamine; Pirimetamina [INN-Spanish]; Pyrimethamine (Pyr); Pyrimethaminum [INN-Latin]; TCMDC-123831; TCMDC-125860; CRL-8131 & Pyrimethamine; CRL-8142 & Pyrimethamine; Fansidar (Pyrimethamine/Sulfadoxine); Pyrimethamine (JAN/USP/INN); Pyrimethamine [USAN:INN:BAN:JAN]; 2,4-Diamino-5-(4-chlorophenyl)-6-ethylpyrimidine; 2,4-Diamino-5-(p-chlorophenyl)-6-ethylpyrimidine; 2,4-Diamino-5-chlorophenyl-6-ethylpyrimidine; 5-(4'-Chlorophenyl)-2,4-diamino-6-ethylpyrimidine; 5-(4-CHLORO-PHENYL)-6-ETHYL-PYRIMIDINE-2,4-DIAMINE; 5-(4-CHLOROPHENYL)-6-ETHYL-2,4-PYRIMIDINEDIAMINE; 5-(4-Chlorophenyl)-6-ethyl-2,4-diaminopyrimidine; 5-(4-Chlorophenyl)-6-ethyl-2,4-pyrimidi nediamine; 5-(4-chlorophenyl)-2,4-diamino-6-ethylpyrimidine; 5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine; 5-(p-chlorophenyl)-6-ethyl-2,4-diaminopyrimidine; 5-[4-Chlorophenyl]-6-ethyl-2,4-pyrimidinediamine

Indication

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[1]
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Therapeutic Class

Antimalarials

Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

248.71

Logarithm of the Partition Coefficient (xlogp)

2.7

Rotatable Bond Count (rotbonds)

2

Hydrogen Bond Donor Count (hbonddonor)

2

Hydrogen Bond Acceptor Count (hbondacc)

4

ADMET Property

BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [2]
Bioavailability: 90% of drug becomes completely available to its intended biological destination(s) [3]
Clearance: The drug present in the plasma can be removed from the body at the rate of 0.052 mL/min/kg [4]
Elimination: 65% of drug is excreted from urine in the unchanged form [2]
Half-life: The concentration or amount of drug in body reduced by one-half in 96 hours [4]
Metabolism: The drug is metabolized via the hepatic []
MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 5.02579 micromolar/kg/day [5]
Unbound Fraction: The unbound fraction of drug in plasma is 0.095% [4]
Vd: Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma 0.43 L/kg [4]
Water Solubility: The ability of drug to dissolve in water is measured as 0.121 mg/mL [2]

Chemical Identifiers

Formula: C12H13ClN4
IUPAC Name: 5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
Canonical SMILES: CCC1=C(C(=NC(=N1)N)N)C2=CC=C(C=C2)Cl
InChI: InChI=1S/C12H13ClN4/c1-2-9-10(11(14)17-12(15)16-9)7-3-5-8(13)6-4-7/h3-6H,2H2,1H3,(H4,14,15,16,17)
InChIKey: WKSAUQYGYAYLPV-UHFFFAOYSA-N

Cross-matching ID

PubChem CID: 4993
ChEBI ID: CHEBI:8673
CAS Number: 58-14-0
DrugBank ID: DB00205
TTD ID: D0C0SK
VARIDT ID: DR01272
ACDINA ID: D00573

Combinatorial Drugs (CBD)

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Repurposed Drugs (RPD)

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Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Folate receptor alpha (FOLR1)	TTVC37M	FOLR1_HUMAN	Modulator	[6]

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Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[7]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[8]

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Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Beta-hexosaminidase subunit beta (HEXB)	OTROYLCR	HEXB_HUMAN	Protein Interaction/Cellular Processes	[9]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Gene/Protein Processing	[10]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Gene/Protein Processing	[10]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Gene/Protein Processing	[11]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Gene/Protein Processing	[11]
Cathepsin B (CTSB)	OTP9G5QB	CATB_HUMAN	Gene/Protein Processing	[11]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Gene/Protein Processing	[12]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Gene/Protein Processing	[13]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Post-Translational Modifications	[14]
HLA class I histocompatibility antigen, alpha chain G (HLA-G)	OTMLK1KN	HLAG_HUMAN	Gene/Protein Processing	[15]

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Molecular Interaction Atlas (MIA)

MIA Detail

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Molecular Expression Atlas of This Drug

The Studied Disease

Malaria

ICD Disease Classification

1F40-1F45

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Folate receptor alpha (FOLR1)	DTT	FOLR1	1.85E-04	-1.41	-1.75
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTP	MATE1	4.05E-01	-5.76E-01	-3.45E-01
Breast cancer resistance protein (ABCG2)	DTP	BCRP	2.10E-01	3.71E-01	7.59E-01

Molecular Expression Atlas (MEA)

MEA Detail

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Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Pyrimethamine (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Sodium bicarbonate	DMMU6BJ	Moderate	Decreased absorption of Pyrimethamine due to adsorption of Sodium bicarbonate.	Acidosis [5C73]	[16]
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Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Beta-D-lactose	E00099	6134	Diluent; Dry powder inhaler carrier; Lyophilization aid
Lactose monohydrate	E00393	104938	Binding agent; Diluent; Dry powder inhaler carrier; Lyophilization aid
Magnesium stearate	E00208	11177	lubricant
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Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Pyrimethamine 25 mg tablet	25 mg	Oral Tablet	Oral

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References

1	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: 4800).
2	BDDCS applied to over 900 drugs
3	Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches
4	Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
5	Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
6	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
7	Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity. Drug Metab Dispos. 2018 May;46(5):592-599.
8	Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates. Cancer Chemother Pharmacol. 2006 Dec;58(6):826-34.
9	Crystal structure of -hexosaminidase B in complex with pyrimethamine, a potential pharmacological chaperone. J Med Chem. 2011 Mar 10;54(5):1421-9. doi: 10.1021/jm101443u. Epub 2011 Jan 25.
10	Palmitate increases the susceptibility of cells to drug-induced toxicity: an in vitro method to identify drugs with potential contraindications in patients with metabolic disease. Toxicol Sci. 2012 Oct;129(2):346-62. doi: 10.1093/toxsci/kfs208. Epub 2012 Jun 14.
11	Pyrimethamine induces apoptosis of melanoma cells via a caspase and cathepsin double-edged mechanism. Cancer Res. 2008 Jul 1;68(13):5291-300. doi: 10.1158/0008-5472.CAN-08-0222.
12	Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s. Drug Metab Dispos. 2001 Jan;29(1):30-5.
13	Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Int J Cancer. 2002 Feb 10;97(5):700-5.
14	Antifolate activity of pyrimethamine enhances temozolomide-induced cytotoxicity in melanoma cells. Mol Cancer Res. 2009 May;7(5):703-12. doi: 10.1158/1541-7786.MCR-08-0263. Epub 2009 May 12.
15	Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
16	Cerner Multum, Inc. "UK Summary of Product Characteristics.".