Discovery of new orally active prostaglandin D sub(2 receptor antagonists)

To identify an orally available drug candidate, a series of 3-benzoylaminophenylacetic acids were synthesized and evaluated as prostaglandin D sub(2 (PGD) sub(2)) receptor antagonists. Some of the compounds tested were found to exhibit excellent inhibitory activity against cAMP accumulation in human...

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Published in:Bioorganic & medicinal chemistry 2011-11, Vol.19 (22), p.6935-6948
Main Authors: Iwahashi, Maki, Naganawa, Atsushi, Kinoshita, Atsushi, Shimabukuro, Atsushi, Nishiyama, Toshihiko, Ogawa, Seiji, Matsunaga, Yoko, Tsukamoto, Kohki, Okada, Yutaka, Matsumoto, Ryoji, Nambu, Fumio, Oumi, Rie, Odagaki, Yoshihiko, Katagi, Jun, Yano, Koji, Tani, Kousuke, Nakai, Hisao, Toda, Masaaki
Format: Article
Language:English
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Summary:To identify an orally available drug candidate, a series of 3-benzoylaminophenylacetic acids were synthesized and evaluated as prostaglandin D sub(2 (PGD) sub(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 sub(2-induced and OVA-induced vascular permeability in guinea pig conjunctiva.)
ISSN:0968-0896
DOI:10.1016/j.bmc.2011.08.065