Design, synthesis and evaluation of polar head group containing 2-keto-oxazole inhibitors of FAAH

Marion Rusch; Stefan Zahov; Ingrid R Vetter; Matthias Lehr; Christian Hedberg

doi:10.1016/j.bmc.2011.11.027

Design, synthesis and evaluation of polar head group containing 2-keto-oxazole inhibitors of FAAH

Bioorg Med Chem. 2012 Jan 15;20(2):1100-12. doi: 10.1016/j.bmc.2011.11.027. Epub 2011 Nov 28.

Authors

Marion Rusch¹, Stefan Zahov, Ingrid R Vetter, Matthias Lehr, Christian Hedberg

Affiliation

¹ Department of Chemical Biology, Max-Planck Institute of Molecular Physiology, Otto-Hahn Strasse 11, D-44227 Dortmund, Germany.

PMID: 22196515
DOI: 10.1016/j.bmc.2011.11.027

Abstract

2-α-Keto oxazoles containing polar head groups in their C5-side chains were designed as fatty acid amide hydrolase (FAAH) inhibitors. Variation in the spacer length resulted in submicromolar α-keto-oxazole FAAH inhibitor (IC(50)=436 nM) presenting electrostatic stabilizing interactions between its polar head group contained in the C5-side chain and the hydrophilic pocket of the enzyme.

MeSH terms

Amidohydrolases / antagonists & inhibitors*
Amidohydrolases / metabolism
Animals
Binding Sites
Computer Simulation
Drug Design*
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Female
Oxazoles / chemical synthesis
Oxazoles / chemistry*
Oxazoles / pharmacology*
Protein Structure, Tertiary
Rats
Rats, Sprague-Dawley
Static Electricity

Substances

Enzyme Inhibitors
Oxazoles
Amidohydrolases
fatty-acid amide hydrolase