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.
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2D Structure
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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
References
1. Cronstein BN. (2005)
Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis.
Pharmacol. Rev., 57 (2): 163-72. [PMID:15914465]
2. Dervieux T, Furst D, Lein DO, Capps R, Smith K, Walsh M, Kremer J. (2004)
Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis.
Arthritis Rheum., 50 (9): 2766-74. [PMID:15457444]
3. Everett BM, Pradhan AD, Solomon DH, Paynter N, Macfadyen J, Zaharris E, Gupta M, Clearfield M, Libby P, Hasan AA et al.. (2013)
Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis.
Am. Heart J., 166 (2): 199-207.e15. [PMID:23895801]
4. Lee YH, Bae SC. (2016)
Association of the ATIC 347 C/G polymorphism with responsiveness to and toxicity of methotrexate in rheumatoid arthritis: a meta-analysis.
Rheumatol. Int., 36 (11): 1591-1599. [PMID:27379764]
5. Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, Sandoval C, Zhao R, Akabas MH, Goldman ID. (2006)
Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption.
Cell, 127 (5): 917-28. [PMID:17129779]
6. Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, Mam V, Hasan A, Rosenberg Y, Iturriaga E et al.. (2019)
Low-Dose Methotrexate for the Prevention of Atherosclerotic Events.
N. Engl. J. Med., 380 (8): 752-762. [PMID:30415610]
7. Rosowsky A, Forsch RA, Wright JE. (2004)
Synthesis and in vitro antifolate activity of rotationally restricted aminopterin and methotrexate analogues.
J. Med. Chem., 47 (27): 6958-63. [PMID:15615544]
8. Rosowsky A, Mota CE, Queener SF, Waltham M, Ercikan-Abali E, Bertino JR. (1995)
2,4-Diamino-5-substituted-quinazolines as inhibitors of a human dihydrofolate reductase with a site-directed mutation at position 22 and of the dihydrofolate reductases from Pneumocystis carinii and Toxoplasma gondii.
J. Med. Chem., 38 (5): 745-52. [PMID:7877140]
9. Zhong W, Zhao L, Liu T, Jiang Z. (2017)
IL-22-producing CD4+T cells in the treatment response of rheumatoid arthritis to combination therapy with methotrexate and leflunomide.
Sci Rep, 7: 41143. [PMID:28117352]