Discovery of new orally active prostaglandin D2 receptor antagonists

被引：4

作者：

Iwahashi, Maki ^{[1
]}

Naganawa, Atsushi ^{[1
]}

Kinoshita, Atsushi ^{[1
]}

Shimabukuro, Atsushi ^{[1
]}

Nishiyama, Toshihiko ^{[1
]}

Ogawa, Seiji ^{[1
]}

Matsunaga, Yoko ^{[1
]}

Tsukamoto, Kohki ^{[1
]}

Okada, Yutaka ^{[1
]}

Matsumoto, Ryoji ^{[2
]}

Nambu, Fumio ^{[1
]}

Oumi, Rie ^{[1
]}

Odagaki, Yoshihiko ^{[1
]}

Katagi, Jun ^{[1
]}

Yano, Koji ^{[1
]}

Tani, Kousuke ^{[1
]}

Nakai, Hisao ^{[1
]}

Toda, Masaaki ^{[1
]}

机构：

[1] Ono Pharmaceut Co Ltd, Minase Res Inst, Osaka 6188585, Japan

[2] Ono Pharmaceut Co Ltd, Osaka 5418526, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2011年 / 19卷 / 22期

关键词：

Prostaglandin; DP receptor; Antagonist; Phenylacetic acid; PROSTANOID RECEPTORS; POTENT;

D O I：

10.1016/j.bmc.2011.08.065

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：6935 / 6948

页数：14

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