2. Academic Validation
  3. Isoquinoline derivatives as potent CRTH2 receptor antagonists: synthesis and SAR

Isoquinoline derivatives as potent CRTH2 receptor antagonists: synthesis and SAR

  • Bioorg Med Chem Lett. 2012 May 1;22(9):3305-10. doi: 10.1016/j.bmcl.2012.03.009.
Rie Nishikawa-Shimono 1,  Yoshinori Sekiguchi,  Takeshi Koami,  Madoka Kawamura,  Daisuke Wakasugi,  Kazuhito Watanabe,  Shunichi Wakahara,  Kayo Matsumoto,  Tetsuo Takayama
Affiliations

Affiliation

  • 1 Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403, Yoshino-Cho, Kita-Ku, Saitama-Shi 331-9530, Japan. [email protected]
PMID: 22469703 DOI: 10.1016/j.bmcl.2012.03.009
Abstract

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 (IC(50)=19 nM) but also excellent functional antagonist activity (IC(50)=13 nM). TASP0376377 was tested for its ability of a chemotaxis assay to show the effectiveness (IC(50)=23 nM), which was in good agreement with the CRTH2 antagonist potency. Furthermore, TASP0376377 showed sufficient selectivity for binding to CRTH2 over the DP1 prostanoid receptor (IC(50)>1 μM) and COX-1 and COX-2 Enzymes (IC(50)>10 μM).

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