Critical modifications of the ISO-1 scaffold improve its potent inhibition of macrophage migration inhibitory factor (MIF) tautomerase activity

Kai Fan Cheng; Yousef Al-Abed

doi:10.1016/j.bmcl.2006.04.038

Critical modifications of the ISO-1 scaffold improve its potent inhibition of macrophage migration inhibitory factor (MIF) tautomerase activity

Bioorg Med Chem Lett. 2006 Jul 1;16(13):3376-9. doi: 10.1016/j.bmcl.2006.04.038. Epub 2006 May 6.

Authors

Kai Fan Cheng¹, Yousef Al-Abed

Affiliation

¹ Department of Medicinal Chemistry, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, 350 Community Drive, Manhasset, NY 11030, USA.

PMID: 16682188
DOI: 10.1016/j.bmcl.2006.04.038

Abstract

Based on the scaffold of (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), an inhibitor of the proinflammatory cytokine MIF, two critical modifications and chiral resolution have significantly improved the potency of the inhibition. Compound (R)-17 is 20-fold more potent than ISO-1 and inhibits MIF tautomerase activity with an IC(50) of 550 nM.

MeSH terms

Enzyme Inhibitors
Intramolecular Oxidoreductases / antagonists & inhibitors*
Isoxazoles / chemical synthesis
Isoxazoles / chemistry
Isoxazoles / pharmacology*
Macrophage Migration-Inhibitory Factors / antagonists & inhibitors*
Molecular Structure
Stereoisomerism
Structure-Activity Relationship

Substances

3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester
Enzyme Inhibitors
Isoxazoles
Macrophage Migration-Inhibitory Factors
Intramolecular Oxidoreductases
dopachrome isomerase