Discovery of a new class of potent, selective, and orally bioavailable CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases
(2008) Journal of Medicinal Chemistry — Vol. 51, n° 7, p. 2227-2243 (2008)
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- Authors
- 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. © 2008 American Chemical Society.
- Affiliations
ESRF, Grenoble (France) Chimie
Citations
Crosignani, S., Page, P., Missotten, M., Colovray, V., Cleva, C., Arrighi, J.-F., Atherall, J., Macritchie, J., Martin, T., Humbert, Y., Gaudet, M., Pupowicz, D., Maio, M., Pittet, P.-A., Golzio, L., Giachetti, C., Rocha, C., Bernardinelli, G., Filinchuk, Y., et al. (2008). Discovery of a new class of potent, selective, and orally bioavailable CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases. Journal of Medicinal Chemistry, 51(7), 2227-2243. https://doi.org/10.1021/jm701383e (Original work published 2008)