Synthesis and SAR studies of benzyl ether derivatives as potent orally active S1P1 agonists
| Autor: | Ikeda Takuya, Toshiyasu Takemoto, Yukiko Sekiguchi, Takashi Kagari, Takaichi Shimozato, Takeshi Fukuda, Taiji Goto, Yumi Kawase, Tsuyoshi Nakamura, Takashi Tsuji, Futoshi Nara, Keisuke Suzuki, Takashi Izumi, Takahide Nishi, Masakazu Tamura, Tomohiro Honda, Shin-ichi Inaba, Takako Kimura, Yumiko Mizuno, Chizuko Yahara |
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| Rok vydání: | 2014 |
| Předmět: |
Stereochemistry
Organic Chemistry Clinical Biochemistry Pharmaceutical Science Biochemistry chemistry.chemical_compound Benzyl ether chemistry Docking (molecular) Oral administration In vivo Drug Discovery Molecular Medicine Homology modeling Ethyl group Selectivity Receptor modulator Molecular Biology |
| Zdroj: | Bioorganic & Medicinal Chemistry. 22:4246-4256 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2014.05.035 |
| Popis: | We report herein the synthesis and structure-activity relationships (SAR) of a series of benzyl ether compounds as an S1P₁ receptor modulator. From our SAR studies, the installation of substituents onto the central benzene ring of 2a was revealed to potently influence the S1P₁ and S1P₃ agonistic activities, in particular, an ethyl group on the 2-position afforded satisfactory S1P₁/S1P₃ selectivity. These changes of the S1P₁ and S1P₃ agonistic activities caused by the alteration of substituents on the 2-position were reasonably explained by a docking study using an S1P₁ X-ray crystal structure and S1P₃ homology modeling. We found that compounds 2b and 2e had a potent in vivo immunosuppressive efficacy along with acceptable S1P₁/S1P₃ selectivity, and confirmed that these compounds had less in vivo bradycardia risk through the evaluation of heart rate change after oral administration of the compounds (30 mg/kg, p.o.) in rats. |
| Databáze: | OpenAIRE |
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