当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Discovery of potent, selective, and orally bioavailable alkynylphenoxyacetic acid CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases.

Discovery of potent, selective, and orally bioavailable alkynylphenoxyacetic acid CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases.

Abstract：

:New phenoxyacetic acid antagonists of CRTH2 are described. Following the discovery of a hit compound by a focused screening, high protein binding was identified as its main weakness. Optimization aimed at reducing serum protein binding led to the identification of several compounds that showed not only excellent affinities for the receptor (41 compounds with K(i) < 10 nM) but also excellent potencies in a human whole blood assay (IC(50) < 100 nM; PGD2-induced eosinophil shape change). Additional optimization of the PK characteristics led to the identification of several compounds suitable for in vivo testing. Of these, 19k and 19s were tested in two different pharmacological models (acute FITC-mediated contact hypersensitivity and ovalbumin-induced eosinophilia models) and found to be active after oral dosing (10 and 30 mg/kg).

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Crosignani S,Prêtre A,Jorand-Lebrun C,Fraboulet G,Seenisamy J,Augustine JK,Missotten M,Humbert Y,Cleva C,Abla N,Daff H,Schott O,Schneider M,Burgat-Charvillon F,Rivron D,Hamernig I,Arrighi JF,Gaudet M,Zimmerli SC,Jui

doi

10.1021/jm200866y

subject

Has Abstract

pub_date

2011-10-27 00:00:00

pages

7299-317

issue

20

eissn

0022-2623

issn

1520-4804

journal_volume

54

pub_type

杂志文章

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