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

S Crosignani, A Prêtre, C Jorand-Lebrun…

Index: Crosignani, Stefano; Pretre, Adeline; Jorand-Lebrun, Catherine; Fraboulet, Gaele; Seenisamy, Jeyaprakashnarayanan; Augustine, John Kallikat; Missotten, Marc; Humbert, Yves; Cleva, Christophe; Abla, Nada; Daff, Hamina; Schott, Olivier; Schneider, Manfred; Burgat-Charvillon, Fabienne; Rivron, Delphine; Hamernig, Ingrid; Arrighi, Jean-Francois; Gaudet, Marilene; Zimmerli, Simone C.; Juillard, Pierre; Johnson, Zoe Journal of Medicinal Chemistry, 2011 , vol. 54, # 20 p. 7299 - 7317

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Citation Number: 25

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 (IC50< 100 ...