Sunday July 05 2009 | Biotechnology feed | All feeds
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Sunday July 05 2009 | Biotechnology feed | All feeds
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PDE4 inhibitors
have attracted considerable interest, particularly in relation to their ability
to treat airway disorders. Of note the launch of Ariflo (cilomilast) is
expected this year. PDE4 inhibitors are potential candidates for the treatment
of other serious conditions including depression and autoimmune diseases, in
particular multiple sclerosis and rheumatoid arthritis. Despite the potential of
PDE4 inhibitors considerable work remains to improve the side effect profile of
such compounds and in particular to limit associated nausea that results from
the inhibition of central PDE4D. The Universite Louis Pasteur is working towards
the development of improved PDE4 inhibitors. In particular,
Universite Louis Pasteur has been optimizing the lead compound
9-(2-fluorobenzyl)-N(6)-methyl-2-trifluoromethyladenine, designing and
synthesizing a new series of 9-substituted derivatives. This new series of
derivatives showed increased PDE4 potency and improved selectivity compared to
other PDE subtypes. Structural modifications were achieved in parallel on three
different positions of the adenine ring, providing key information on key
moieties and on lead optimization strategies. The most potent inhibitors within
this series inhibited PDE4 with IC50 values as low as 0.096 nM. Furthermore
potency at the PDE4 subtype was 50,000-150,000 times greater than for other PDE
families. Functionally, these new derivatives showed improved efficiency in
inhibiting the TNFalpha release from mononuclear cells from healthy subjects and
are among the most potent and selective PDE4 inhibitors reported so far. Further studies
are eagerly awaited that may allow the further development of these and related
molecules towards the clinic. Adapted from Raboisson et al, Eur J Med Chem 2003 Feb;38(2):199-214 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.
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