Author/Authors :
Ippei Sato، نويسنده , , Koichiro Morihira، نويسنده , , Hiroshi Inami، نويسنده , , Hirokazu Kubota، نويسنده , , Tatsuaki Morokata، نويسنده , , Keiko Suzuki، نويسنده , , Yosuke Iura، نويسنده , , Aiko Nitta، نويسنده , , Takayuki Imaoka، نويسنده , , Toshiya Takahashi، نويسنده , , Makoto Takeuchi، نويسنده , , Mitsuaki Ohta، نويسنده , , Shin-ichi Tsukamoto، نويسنده ,
Abstract :
In our previous study on discovering novel types of CCR3 antagonists, we found a fluoronaphthalene derivative (1) that exhibited potent CCR3 inhibitory activity with an IC50 value of 20 nM. However, compound 1 also inhibited human cytochrome P450 2D6 (CYP2D6) with an IC50 value of 400 nM. In order to reduce its CYP2D6 inhibitory activity, we performed further systematic structural modifications on 1. In particular, we focused on reducing the number of lipophilic moieties in the biphenyl part of 1, using C log D7.4 values as the reference index of lipophilicity. This research led to the identification of N-{(3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-(piperidin-1-ylcarbonyl)isonicotinamide 1-oxide (30) which showed comparable CCR3 inhibitory activity (IC50 = 23 nM) with much reduced CYP2D6 inhibitory activity (IC50 = 29,000 nM) compared with 1.
