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Bioorg Med Chem. 2011 Nov 15;19(22):6935-48. doi: 10.1016/j.bmc.2011.08.065. Epub 2011 Sep 2.

Discovery of new orally active prostaglandin D2 receptor antagonists.

Author information

1
Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka, Japan. iwahashi@ono.co.jp

Abstract

To identify an orally available drug candidate, a series of 3-benzoylaminophenylacetic acids were synthesized and evaluated as prostaglandin D(2) (PGD(2)) receptor antagonists. Some of the compounds tested were found to exhibit excellent inhibitory activity against cAMP accumulation in human platelet rich plasma (hPRP), which is one of the indexes of DP antagonism. The optimization process including improvement of the physicochemical properties such as solubility, which may result in an improved pharmacokinetic (PK) profile, is presented. Optimized compounds were studied for their pharmacokinetics and in vivo potential. A structure-activity relationship study is also presented. Some of the test compounds were found to have in vivo efficacy towards the inhibition of PGD(2)-induced and OVA-induced vascular permeability in guinea pig conjunctiva.

PMID:
21982795
DOI:
10.1016/j.bmc.2011.08.065
[Indexed for MEDLINE]

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