Design and synthesis of 6-fluoro-2-naphthyl derivatives as novel CCR3 antagonists with reduced CYP2D6 inhibition
| Autor: | Tatsuaki Morokata, Hirokazu Kubota, Keiko Suzuki, Takayuki Imaoka, Koichiro Morihira, Yosuke Iura, Mitsuaki Ohta, Toshiya Takahashi, Makoto Takeuchi, Aiko Nitta, Hiroshi Inami, Shin-ichi Tsukamoto, Ippei Sato |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
CYP2D6
Cytoplasm Hydrocarbons Fluorinated Stereochemistry Receptors CCR3 Clinical Biochemistry CCR3 Pharmaceutical Science Naphthalenes Inhibitory postsynaptic potential Biochemistry chemistry.chemical_compound Inhibitory Concentration 50 Structure-Activity Relationship Cytochrome P-450 CYP2D6 Inhibitors Drug Discovery Humans Isonicotinamide Molecular Biology IC50 Biphenyl Chemistry Organic Chemistry Drug Design Lipophilicity Molecular Medicine Calcium Human cytochrome |
| Zdroj: | Bioorganicmedicinal chemistry. 16(18) |
| ISSN: | 1464-3391 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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