Isoquinoline derivatives as potent CRTH2 receptor antagonists: Synthesis and SAR

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 9; pp. 3305 - 3310
• Main Authors: Nishikawa-Shimono, Rie, Sekiguchi, Yoshinori, Koami, Takeshi, Kawamura, Madoka, Wakasugi, Daisuke, Watanabe, Kazuhito, Wakahara, Shunichi, Matsumoto, Kayo, Takayama, Tetsuo
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.2012
• Subjects: Allergic diseases; antagonists; binding capacity; Chemotaxis; CRTH2 antagonist; enzymes; Inhibitory Concentration 50; Isoquinoline; Isoquinolines - chemistry; Isoquinolines - pharmacology; Models, Molecular; PGD2; Prostaglandin-Endoperoxide Synthases - chemistry; Protein Binding; Protein Interaction Domains and Motifs; Receptors, Immunologic - antagonists & inhibitors; Receptors, Prostaglandin - antagonists & inhibitors; Receptors, Prostaglandin - chemistry; Structure-Activity Relationship; structure-activity relationships; PGD2; Isoquinoline; Allergic diseases; CRTH2 antagonist
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.03.009

Synthesis and structure–activity relationship of a novel series of isoquinoline CRTH2 receptor antagonists are described. One of the most potent compounds, TASP0376377 (6m), showed not only potent binding affinity (IC50=19nM) but also excellent functional antagonist activity (IC50=13nM). TASP0376377 was tested for its ability of a chemotaxis assay to show the effectiveness (IC50=23nM), which was in good agreement with the CRTH2 antagonist potency. Furthermore, TASP0376377 showed sufficient selectivity for binding to CRTH2 over the DP1 prostanoid receptor (IC50>1μM) and COX-1 and COX-2 enzymes (IC50>10μM).