Discovery of a Novel Series of CRTH2 (DP2) Receptor Antagonists Devoid of Carboxylic Acids
journal contribution
posted on 2011-12-08, 00:00 authored by Stefano Crosignani, Catherine Jorand-Lebrun, Gordon Campbell, Adeline Prêtre, Tania Grippi-Vallotton, Anna Quattropani, Gwenaelle Bouscary-Desforges, Agnes Bombrun, Marc Missotten, Yves Humbert, Christèle Frémaux, Mikaël Pâquet, Kamel El Harkani, Charles G. Bradshaw, Christophe Cleva, Nada Abla, Hamina Daff, Olivier Schott, Pierre-André Pittet, Jean-François Arrighi, Marilène Gaudet, Zoë JohnsonAntagonism of the CRTH2 receptor represents a very attractive
target
for a variety of allergic diseases. Most CRTH2 antagonists known to
date possess a carboxylic acid moiety, which is essential for binding.
However, potential acid metabolites O-acyl glucuronides
might be linked to idiosynchratic toxicity in humans. In this communication,
we describe a new series of compounds that lack the carboxylic acid
moiety. Compounds with high affinity (Ki < 10 nM) for the receptor have been identified. Subsequent optimization
succeeded in reducing the high metabolic clearance of the first compounds
in human and rat liver microsomes. At the same time, inhibition of
the CYP isoforms was optimized, giving rise to stable compounds with
an acceptable CYP inhibition profile (IC50 CYP2C9 and 2C19
> 1 μM). Taken together, these data show that compounds devoid
of carboxylic acid groups could represent an interesting alternative
to current CRTH2 antagonists in development.
