Document Report Card

ID: ALA1145542

Journal: J Med Chem

Title: Discovery of a new class of potent, selective, and orally bioavailable CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases.

Authors: Crosignani S, Page P, Missotten M, Colovray V, Cleva C, Arrighi JF, Atherall J, Macritchie J, Martin T, Humbert Y, Gaudet M, Pupowicz D, Maio M, Pittet PA, Golzio L, Giachetti C, Rocha C, Bernardinelli G, Filinchuk Y, Scheer A, Schwarz MK, Chollet A.

Abstract: A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound ( 5) was found during a high-throughput screening campaign. Structure-activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds ( R)- 58 and ( R)- 71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug.

CiteXplore: 18318469

DOI: 10.1021/jm701383e