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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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Sato I,Morihira K,Inami H,Kubota H,Morokata T,Suzuki K,Iura Y,Nitta A,Imaoka T,Takahashi T,Takeuchi M,Ohta M,Tsukamoto S

doi

10.1016/j.bmc.2008.08.006

subject

Has Abstract

pub_date

2008-09-15 00:00:00

pages

8607-18

issue

18

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(08)00722-0

journal_volume

16

pub_type

杂志文章

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