Synthesis and structure–activity relationships of N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide derivatives as novel CCR3 antagonists

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• 作者：Ippei Sato ; Koichiro Morihira ; Hiroshi Inami ; Hirokazu Kubota ; Tatsuaki Morokata ; Keiko Suzuki ; Noritaka Hamada ; Yosuke Iura ; Aiko Nitta ; Takayuki Imaoka ; Toshiya Takahashi ; Makoto Takeuchi ; Mitsuaki
• 关键词：Allergic diseases ; CCR3 antagonists ; 6-fluoro-2-naphthylmethyl moiety ; Nortropane derivatives
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 出版时间：1 January 2008
• 年：2008
• 卷：16
• 期：1
• 页码：144-156
• 全文大小：372 K

文摘

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.