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

Isoquinoline derivatives as potent CRTH2 antagonists: design, synthesis and SAR

  • Bioorg Med Chem. 2013 Dec 15;21(24):7674-85. doi: 10.1016/j.bmc.2013.10.025.
Rie Nishikawa-Shimono 1,  Yoshinori Sekiguchi,  Takeshi Koami,  Madoka Kawamura,  Daisuke Wakasugi,  Kazuhito Watanabe,  Shunichi Wakahara,  Kayo Kimura,  Susumu Yamanobe,  Tetsuo Takayama
Affiliations

Affiliation

  • 1 Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403, Yoshino-Cho, Kita-Ku, Saitama-Shi 331-9530, Japan. Electronic address: [email protected].
PMID: 24216094 DOI: 10.1016/j.bmc.2013.10.025
Abstract

In this study, we describe the synthesis and structure-activity relationship (SAR) of a series of isoquinoline chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonists. TASP0376377 (15-20), one of the most potent compounds, showed a potent binding affinity (IC50=19 nM) in addition to the excellent functional antagonist activity (IC50=13 nM). Moreover, the efficacy of this compound in a chemotaxis assay (IC50=23 nM) was in good agreement with its potency as a CRTH2 antagonist. In addition, 15-20 exhibited greater selectivity in binding to CRTH2 than to the DP1 prostanoid receptor (IC50 >1 μM) or the enzymes COX-1 and COX-2 (IC50 >10 μM).

Keywords

Allergic diseases; CRTH2 antagonist; Isoquinoline; PGD2.

Figures
Products