Synthesis and structure-activity relationships of N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide derivatives as novel CCR3 antagonists.
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 Ca(2+) 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 exo-N-{8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3- yl}biphenyl-2-carboxamide [corrected] (31) as a potent CCR3 antagonist with an IC(50) value of 0.020 microM.
Sato
Ippei
I
Drug Discovery Research, Astellas Pharma Inc., 21Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. ippei.sato@jp.astellas.com
Morihira
Koichiro
K
Inami
Hiroshi
H
Kubota
Hirokazu
H
Morokata
Tatsuaki
T
Suzuki
Keiko
K
Hamada
Noritaka
N
Iura
Yosuke
Y
Nitta
Aiko
A
Imaoka
Takayuki
T
Takahashi
Toshiya
T
Takeuchi
Makoto
M
Ohta
Mitsuaki
M
Tsukamoto
Shin-ichi
S
D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D054413:Chemokine CCL11; D006801:Humans; D020128:Inhibitory Concentration 50; D054448:Precursor Cells, B-Lymphoid; D054397:Receptors, CCR3 / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
D001549:Benzamides; D054413:Chemokine CCL11; D054397:Receptors, CCR3; D054852:Small Molecule Libraries; D002118:Calcium