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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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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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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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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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
Immunopharmacology Comments
CH-4051 is a metabolically inert antifolate MTX analogue that was evaluated as an anti-rheumatoid arthritis therapeutic. It reached Phase 2 trial, but development appears to have halted.
Immunopharmacology Disease
Disease X-Refs Comment References
Rheumatoid arthritis Disease Ontology: DOID:7148
OMIM: 180300
 CH-4501 completed Phase 2 trial in RA- see NCT01116141