CH-4051   Click here for help

GtoPdb Ligand ID: 9844

Synonyms: Formula (10) [WO2012078708A1]
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: CH-4051 is an orally available methotrexate (MTX) analogue that is designed to resist metabolic degradation [4-5]. This strategy was employed to improve the safety and tolerability profile compared to MTX, since a significant proportion of the toxicity profile of MTX can be attributed to its polyglutamylated and hydroxylated metabolites. Like MTX, CH-4051 has anti-inflammatory, autoimmune and anti-tumour properties and is a potent inhibitor of dihydrofolate reductase, an enzyme required for cell proliferation. The racemic mixture of CH-4051, known as CH-1405 (represented by the non-chiral structure in PubChem CID 9846537) [3], completed Phase 2 development for rheumatoid arthritis, and exhibited comparable efficacy to MTX [1-2]. Structurally, CH-4051 is the more active L-4'-methylene-glutamic acid containing diastereomer (or S-enantiomer) of CH-1405 [5].
2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 10
Hydrogen bond donors 5
Rotatable bonds 10
Topological polar surface area 181.52
Molecular weight 449.17
XLogP -0.01
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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Canonical SMILES OC(=O)C(NC(=O)c1ccc(cc1)CCc1ccc2c(c1)c(N)nc(n2)N)CC(=C)C(=O)O
Isomeric SMILES OC(=O)[C@@H](NC(=O)c1ccc(cc1)CCc1ccc2c(c1)c(N)nc(n2)N)CC(=C)C(=O)O
InChI InChI=1S/C23H23N5O5/c1-12(21(30)31)10-18(22(32)33)26-20(29)15-7-4-13(5-8-15)2-3-14-6-9-17-16(11-14)19(24)28-23(25)27-17/h4-9,11,18H,1-3,10H2,(H,26,29)(H,30,31)(H,32,33)(H4,24,25,27,28)/t18-/m0/s1
InChI Key NAWXUBYGYWOOIX-SFHVURJKSA-N
References
1. Bajpai M. (2010)
CH-1504, a metabolically inert antifolate for the potential treatment of rheumatoid arthritis.
IDrugs, 13 (8): 559-67. [PMID:20721827]
2. Keystone EC, Shirinsky VS, Simon LS, Pedder S, Hewitt LA, CH-1504 Study Group. (2011)
Efficacy and safety of CH-1504, a metabolically stable antifolate, in patients with active rheumatoid arthritis: results of a phase II multicenter randomized study.
J Rheumatol, 38 (9): 1875-83. [PMID:21724705]
3. McGuire JJ, Haile WH. (2009)
Metabolism-blocked antifolates as potential anti-rheumatoid arthritis agents: 4-amino-4-deoxy-5,8,10-trideazapteroyl-d,l-4'-methyleneglutamic acid (CH-1504) and its analogs.
Biochem Pharmacol, 77 (7): 1161-72. [PMID:19174154]
4. Pimplaskar HK, Lebedev M, Horvath K. (2009)
Crystalline salt forms of antifolate compounds and methods of manufacturing thereof.
Patent number: WO2009126639A1. Assignee: Chelsea Therapeutics, Inc.. Priority date: 07/04/2008. Publication date: 15/10/2009.
5. Roberts MJ, Rowse G. (2012)
Combination comprising methotrexate and an antifolate compound.
Patent number: WO2012078708A1. Assignee: Chelsea Therapeutics, Inc.. Priority date: 07/12/2010. Publication date: 14/06/2012.