Prodrugs of fumarate esters for the treatment of psoriasis and multiple sclerosis--a computational approach.

Abstract

Density functional theory (DFT) calculations at B3LYP/6-31 G (d,p) and B3LYP/6-311+G(d,p) levels for the substituted pyridine-catalyzed isomerization of monomethyl maleate revealed that isomerization proceeds via four steps, with the rate-limiting step being proton transfer from the substituted pyridinium ion to the C=C double bond in INT1. In addition, it was found that the isomerization rate (maleate to fumarate) is solvent dependent. Polar solvents, such as water, tend to accelerate the isomerization rate, whereas apolar solvents, such as chloroform, act to slow down the reaction. A linear correlation was obtained between the isomerization activation energy and the dielectric constant of the solvent. Furthermore, linearity was achieved when the activation energy was plotted against the pKa value of the catalyst. Substituted-pyridine derivatives with high pKa values were able to catalyze isomerization more efficiently than those with low pKa values. The calculated relative rates for prodrugs 1-6 were: 1 (406.7), 2 (7.6×10(6)), 3 (1.0), 4 (20.7), 5 (13.5) and 6 (2.2×10(3)). This result indicates that isomerizations of prodrugs 1 and 3-5 are expected to be slow and that of prodrugs 2 and 6 are expected to be relatively fast. Hence, prodrugs 2 and 3-5 have the potential to be utilized as prodrugs for the slow release of monomethylfumarate in the treatment of psoriasis and multiple sclerosis.

• Authors: Rafik Karaman, Ghadeer Dokmak, Maryam Bader, Hussein Hallak, Mustafa Khamis, Laura Scrano, Sabino Aurelio Bufo
• Journal: Journal of molecular modeling (J Mol Model) Vol. 19 Issue 1 Pg. 439-52 (Jan 2013) ISSN: 0948-5023 [Electronic] Germany
• PMID: 22940872 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fumarates
• Maleates
• Prodrugs
• Pyridines
• Solvents
• citraconic acid

Topics

• Catalysis
• Computer Simulation
• Fumarates (chemistry, therapeutic use)
• Humans
• Isomerism
• Kinetics
• Maleates (chemistry)
• Models, Molecular
• Multiple Sclerosis (drug therapy)
• Prodrugs (chemistry, therapeutic use)
• Psoriasis (drug therapy)
• Pyridines (chemistry)
• Quantum Theory
• Solvents
• Thermodynamics