methotrexate   

GtoPdb Ligand ID: 4815

Synonyms: Abitrexate® | amethopterin | Nordimet® | Rasuvo®
methotrexate is an approved drug (FDA (1953), EMA (2016))
Compound class: Synthetic organic
Comment: Methotrexate is a folate (folic acid) analogue that is classified as an antimetabolite and antifolate drug, and a disease-modifying anti-rheumatic drug (DMARD). It is used clinically for its antiproliferative and anti-inflammatory effects. The primary action of methotrexate is inhibition of the enzyme dihydrofolate reductase (DHFR). DHFR is essential for the production of precursors that are required for de novo purine synthesis.
IUPHAR Pharmacology Education Project (PEP) logo

View more information in the IUPHAR Pharmacology Education Project: methotrexate

2D Structure
Click here for structure editor
Physico-chemical Properties
Hydrogen bond acceptors 13
Hydrogen bond donors 5
Rotatable bonds 10
Topological polar surface area 210.54
Molecular weight 454.17
XLogP -2.67
No. Lipinski's rules broken 1
SMILES / InChI / InChIKey
Canonical SMILES OC(=O)CCC(C(=O)O)NC(=O)c1ccc(cc1)N(Cc1cnc2c(n1)c(N)nc(n2)N)C
Isomeric SMILES OC(=O)CC[C@@H](C(=O)O)NC(=O)c1ccc(cc1)N(Cc1cnc2c(n1)c(N)nc(n2)N)C
InChI InChI=1S/C20H22N8O5/c1-28(9-11-8-23-17-15(24-11)16(21)26-20(22)27-17)12-4-2-10(3-5-12)18(31)25-13(19(32)33)6-7-14(29)30/h2-5,8,13H,6-7,9H2,1H3,(H,25,31)(H,29,30)(H,32,33)(H4,21,22,23,26,27)/t13-/m0/s1
InChI Key FBOZXECLQNJBKD-ZDUSSCGKSA-N
Immunopharmacology Comments
Methotrexate is a DMARD prescribed for rheumatoid arthritis, psoriatic arthritis and vasculitis. In inflammation its mode of action relates to its ability to inhibit folate pathway enzymes, including aminoimidazole carboxamide adenosine ribonucleotide transformylase (ATIC; P31939). In vivo conversion of methotrexate to methotrexate-polyglutamates is required for ATIC inhibition [2]. ATIC inhibition leads to intracellular accumulation of its substrate aminoimidazole carboxamide adenosine ribonucleotide (AICAR), increased adenosine release and modulation of immune cell (neutrophils, natural killer cells, monocytes/macrophages and T cells) function, effects which ultimately produce a potent anti-inflammatory effect [1,4]. Key inflammatory mediators such as IL-17, IL-22, IL-23 and CCL20 are downregulated by methotrexate.

Low-dose methotrexate was evaluated to determine if inflammation inhibition could provide an effective approach for the secondary prevention of atherosclerotic events (heart attack, stroke, and cardiovascular death) in the phase 3 Cardiovascular Inflammation Reduction Trial (CIRT; NCT01594333) [3]. Analysis of results from CIRT concluded that methotrexate was no more effective than placebo in patients with stable atherosclerosis; it did not reduce the number of cardiovascular events, or reduce inflammation markers such as IL-1β, IL-6 and C-reactive protein, relative to placebo-treated controls [6].
Immunopharmacology Disease
Disease X-Refs Comment References
Vasculitis Disease Ontology: DOID:865
Approved drug for vasculitis.
Rheumatoid arthritis Disease Ontology: DOID:7148
OMIM: 180300
Approved drug for RA.
Psoriatic arthritis Disease Ontology: DOID:9008
Approved drug for PsA.
Juvenile idiopathic arthritis Oral solution of methotrexate approved for JIA in pediatric pateints.
Immunopaedia Case Studies Links
My eyes cross at twilight
14 year old with severe hip pain
A 7 year old with severe muscle weakness and difficulty walking
A case of scaly annular plaques
Case of eye injury and decreased vision