Isoquinoline derivatives as potent CRTH2 antagonists: design, synthesis and SAR.
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).
Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403, Yoshino-Cho, Kita-Ku, Saitama-Shi 331-9530, Japan. Electronic address: r-nishikawa@so.taisho.co.jp.
Rie
R
Nishikawa-Shimono
Yoshinori
Y
Sekiguchi
Takeshi
T
Koami
Madoka
M
Kawamura
Daisuke
D
Wakasugi
Kazuhito
K
Watanabe
Shunichi
S
Wakahara
Kayo
K
Kimura
Susumu
S
Yamanobe
Tetsuo
T
Takayama
D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D018418:Th2 Cells
D007546:Isoquinolines; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C039109:isoquinoline; C036293:prostaglandin D2 receptor
Allergic diseases; CRTH2 antagonist; Isoquinoline; PGD2