title: Design and synthesis of 6-fluoro-2-naphthyl derivatives as novel CCR3 antagonists with reduced CYP2D6 inhibition.
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 IC(50) value of 20 nM. However, compound 1 also inhibited human cytochrome P450 2D6 (CYP2D6) with an IC(50) 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 ClogD(7.4) 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 (IC(50)=23 nM) with much reduced CYP2D6 inhibitory activity (IC(50)=29,000 nM) compared with 1.
authors.affiliation: Drug Discovery Research, Astellas Pharma. Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Ippei
authors.initials: I
authors.lastname: Sato
authors.forename: Koichiro
authors.initials: K
authors.lastname: Morihira
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inami
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kubota
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Morokata
authors.forename: Keiko
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Iura
authors.forename: Aiko
authors.initials: A
authors.lastname: Nitta
authors.forename: Takayuki
authors.initials: T
authors.lastname: Imaoka
authors.forename: Toshiya
authors.initials: T
authors.lastname: Takahashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Tsukamoto