1. Eur J Med Chem. 2010 Sep;45(9):3564-74. Epub 2010 May 11.

Chemistry around imidazopyrazine and ibuprofen: discovery of novel fatty acid
amide hydrolase (FAAH) inhibitors.

De Wael F, Muccioli GG, Lambert DM, Sergent T, Schneider YJ, Rees JF,
Marchand-Brynaert J.

Institute of Condensed Matter and Nanoscience, Unité de chimie organique et
médicinale, Université catholique de Louvain, Place Louis Pasteur 1, B-1348
Louvain-la-Neuve, Belgium.

Based on the imidazo-[1,2-a]-pyrazin-3-(7H)-one scaffold, a dual action prodrug
has been designed for combining antioxidant and anti-inflammatory activities,
possibly unmasked upon oxidation. The construction of the target-molecule
requires two building blocks, namely a 2-amino-1,4-pyrazine and a 2-ketoaldehyde.
Attempts to synthesize the 2-ketoaldehyde (5a) derived from ibuprofen failed, but
led to the corresponding 2-ketoaldoxime (7a) which could not be condensed with
the pyrazine synthons. However, a model compound, i.e. phenylglyoxal aldoxime,
reacted well under microwave activation to furnish novel
imidazo[1,2-a]-pyrazine-3-(7H)-imine derivatives (18a,b). These heterobicycles
behave as antioxidants by inhibiting the lipid peroxidation, and one compound
(18b) is endowed with a significant anti-inflammatory effect in a cellular test. 
Unexpectedly, all the synthetic intermediates derived from ibuprofen are good
inhibitors of FAAH, the most active compound (4a) featuring the 1,3-dithian-2-yl 
motif.


PMID: 20570023 [PubMed - in process]