Author/Authors :
Ippei Sato، نويسنده , , Koichiro Morihira، نويسنده , , Hiroshi Inami، نويسنده , , Hirokazu Kubota، نويسنده , , Tatsuaki Morokata، نويسنده , , Keiko Suzuki، نويسنده , , Noritaka Hamada، نويسنده , , Yosuke Iura، نويسنده , , Aiko Nitta، نويسنده , , Takayuki Imaoka، نويسنده , , Toshiya Takahashi، نويسنده , , Makoto Takeuchi، نويسنده , , Mitsuaki Ohta، نويسنده , , Shin-ichi Tsukamoto، نويسنده ,
Abstract :
A novel class of potent CCR3 receptor antagonists were designed and synthesized starting from N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide (1),which was found by subjecting our chemical library to high throughput screening (HTS). The CCR3 inhibitory activity of the synthesized compounds against eotaxin-induced Ca2+ influx was evaluated using CCR3-expressing preB cells. Systematic chemical modifications of 1 revealed that the 6-fluoro-2-naphthylmethyl moiety was essential for CCR3 inhibitory activity in this new series of CCR3 antagonists. Further structural modifications of the benzamide and piperidine moieties of 1 led to the identification of N-{8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3- yl}biphenyl-2-carboxamide (31) as a potent CCR3 antagonist with an IC50 value of 0.020 μM.
Keywords :
CCR3 antagonists , Nortropane derivatives , 6-fluoro-2-naphthylmethyl moiety , Allergic diseases
