title: Discovery of new orally active prostaglandin D2 receptor antagonists.
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.
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka, Japan. iwahashi@ono.co.jp
authors: Maki
authors: M
authors: Iwahashi
authors: Atsushi
authors: A
authors: Naganawa
authors: Atsushi
authors: A
authors: Kinoshita
authors: Atsushi
authors: A
authors: Shimabukuro
authors: Toshihiko
authors: T
authors: Nishiyama
authors: Seiji
authors: S
authors: Ogawa
authors: Yoko
authors: Y
authors: Matsunaga
authors: Kohki
authors: K
authors: Tsukamoto
authors: Yutaka
authors: Y
authors: Okada
authors: Ryoji
authors: R
authors: Matsumoto
authors: Fumio
authors: F
authors: Nambu
authors: Rie
authors: R
authors: Oumi
authors: Yoshihiko
authors: Y
authors: Odagaki
authors: Jun
authors: J
authors: Katagi
authors: Koji
authors: K
authors: Yano
authors: Kousuke
authors: K
authors: Tani
authors: Hisao
authors: H
authors: Nakai
authors: Masaaki
authors: M
authors: Toda
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006168:Guinea Pigs; D006801:Humans; D008958:Models, Molecular; D010648:Phenylacetates / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D010648:Phenylacetates; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor