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

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

  • J Med Chem. 2008 Apr 10;51(7):2227-43. doi: 10.1021/jm701383e.
Stefano Crosignani 1,  Patrick Page,  Marc Missotten,  Véronique Colovray,  Christophe Cleva,  Jean-François Arrighi,  John Atherall,  Jackie Macritchie,  Thierry Martin,  Yves Humbert,  Marilène Gaudet,  Doris Pupowicz,  Maurizio Maio,  Pierre-André Pittet,  Lucia Golzio,  Claudio Giachetti,  Cynthia Rocha,  Gérald Bernardinelli,  Yaroslav Filinchuk,  Alexander Scheer,  Matthias K Schwarz,  André Chollet
Affiliations

Affiliation

  • 1 Merck Serono International S.A., 9 chemin des Mines, Geneva, Switzerland.
PMID: 18318469 DOI: 10.1021/jm701383e
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.

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