title: Isoquinoline derivatives as potent CRTH2 receptor antagonists: synthesis and SAR.
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).
authors.affiliation: Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403, Yoshino-Cho, Kita-Ku, Saitama-Shi 331-9530, Japan. rie.nishikawa@po.rd.taisho.co.jp
authors.forename: Rie
authors.initials: R
authors.lastname: Nishikawa-Shimono
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Sekiguchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Koami
authors.forename: Madoka
authors.initials: M
authors.lastname: Kawamura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Wakasugi
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Watanabe
authors.forename: Shunichi
authors.initials: S
authors.lastname: Wakahara
authors.forename: Kayo
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takayama
mesh_terms: D002633:Chemotaxis; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D007546:Isoquinolines; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C501562:prostanoid D receptor 1, human; D011451:Prostaglandin-Endoperoxide Synthases; C036293:prostaglandin D2 receptor