Discovery of potent, selective, and orally bioavailable alkynylphenoxyacetic acid CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases.

Stefano Crosignani, Adeline Prêtre, Catherine Jorand-Lebrun, Gaële Fraboulet, Jeyaprakashnarayanan Seenisamy, John Kallikat Augustine, Marc Missotten, Yves Humbert, Christophe Cleva, Nada Abla, Hamina Daff, Olivier Schott, Manfred Schneider, Fabienne Burgat-Charvillon, Delphine Rivron, Ingrid Hamernig, Jean-François Arrighi, Marilène Gaudet, Simone C Zimmerli, Pierre Juillard, Zoe Johnson

Index: J. Med. Chem. 20th ed., 54 , 7299-7317, (2011)

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Abstract

New phenoxyacetic acid antagonists of CRTH2 are described. Following the discovery of a hit compound by a focused screening, high protein binding was identified as its main weakness. Optimization aimed at reducing serum protein binding led to the identification of several compounds that showed not only excellent affinities for the receptor (41 compounds with K(i) < 10 nM) but also excellent potencies in a human whole blood assay (IC(50) < 100 nM; PGD2-induced eosinophil shape change). Additional optimization of the PK characteristics led to the identification of several compounds suitable for in vivo testing. Of these, 19k and 19s were tested in two different pharmacological models (acute FITC-mediated contact hypersensitivity and ovalbumin-induced eosinophilia models) and found to be active after oral dosing (10 and 30 mg/kg).