Synthesis and SAR studies of benzyl ether derivatives as potent orally active S1P1 agonists
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 act...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2014-08, Vol.22 (15), p.4246-4256 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Tsuji, Takashi Suzuki, Keisuke Nakamura, Tsuyoshi Goto, Taiji Sekiguchi, Yukiko Ikeda, Takuya Fukuda, Takeshi Takemoto, Toshiyasu Mizuno, Yumiko Kimura, Takako Kawase, Yumi Nara, Futoshi Kagari, Takashi Shimozato, Takaichi Yahara, Chizuko Inaba, Shinichi Honda, Tomohiro Izumi, Takashi Tamura, Masakazu Nishi, Takahide |
| description | 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 (30mg/kg, p.o.) in rats. |
| doi_str_mv | 10.1016/j.bmc.2014.05.035 |
| format | Article |
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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 (30mg/kg, p.o.) in rats.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2014.05.035</identifier><identifier>PMID: 24909680</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Administration, Oral ; Animals ; Binding Sites ; Bradycardia ; Ethers - chemistry ; Ethers - pharmacokinetics ; Ethers - therapeutic use ; Graft Rejection - prevention & control ; Half-Life ; Heart Rate - drug effects ; HvGR ; Immunosuppressive Agents - chemistry ; Immunosuppressive Agents - pharmacology ; Immunosuppressive Agents - therapeutic use ; Lymphocyte ; Male ; Modeling ; Molecular Docking Simulation ; Protein Structure, Tertiary ; Rats ; Rats, Inbred Lew ; Receptors, Lysosphingolipid - agonists ; Receptors, Lysosphingolipid - metabolism ; S1P1 receptor agonist ; Structure-Activity Relationship ; Transplantation, Homologous</subject><ispartof>Bioorganic & medicinal chemistry, 2014-08, Vol.22 (15), p.4246-4256</ispartof><rights>2014 Elsevier Ltd</rights><rights>Copyright © 2014 Elsevier Ltd. 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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 (30mg/kg, p.o.) in rats.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Bradycardia</subject><subject>Ethers - chemistry</subject><subject>Ethers - pharmacokinetics</subject><subject>Ethers - therapeutic use</subject><subject>Graft Rejection - prevention & control</subject><subject>Half-Life</subject><subject>Heart Rate - drug effects</subject><subject>HvGR</subject><subject>Immunosuppressive Agents - chemistry</subject><subject>Immunosuppressive Agents - pharmacology</subject><subject>Immunosuppressive Agents - therapeutic use</subject><subject>Lymphocyte</subject><subject>Male</subject><subject>Modeling</subject><subject>Molecular Docking Simulation</subject><subject>Protein Structure, Tertiary</subject><subject>Rats</subject><subject>Rats, Inbred Lew</subject><subject>Receptors, Lysosphingolipid - agonists</subject><subject>Receptors, Lysosphingolipid - metabolism</subject><subject>S1P1 receptor agonist</subject><subject>Structure-Activity Relationship</subject><subject>Transplantation, Homologous</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEFPGzEQha2qCELgB_RS-djLLjPr9e5aPUWIFiQkEKEnDpZjT1pHm93UdiKFX19HoRw5zeF970nzMfYFoUTA5mpVLta2rADrEmQJQn5iE6ybuhBC4Wc2AdV0BXSqOWPnMa4AoKoVnrKzfA4ZTNjLfD-kPxR95GZwfD574jFtnafIxyVf0PC67zllInBHwe9M8rucmcg3Y6Ih8TGYvt9zYw8Bn-MjcvN7HHxM8YKdLE0f6fLtTtmvHzfP17fF_cPPu-vZfWGrpkuFsVZYQdAu60YqaJ2hRomqdUq5ThqoAahCQ7UUDTlEiUI6Aa3qWlkJBWLKvh13N2H8u6WY9NpHS31vBhq3UaPMX3fYSZFRPKI2jDEGWupN8GsT9hpBH5zqlc5O9cGpBqmz09z5-ja_XazJvTf-S8zA9yNA-cmdp6Cj9TRYcj6QTdqN_oP5f_elheM</recordid><startdate>20140801</startdate><enddate>20140801</enddate><creator>Tsuji, Takashi</creator><creator>Suzuki, Keisuke</creator><creator>Nakamura, Tsuyoshi</creator><creator>Goto, Taiji</creator><creator>Sekiguchi, Yukiko</creator><creator>Ikeda, Takuya</creator><creator>Fukuda, Takeshi</creator><creator>Takemoto, Toshiyasu</creator><creator>Mizuno, Yumiko</creator><creator>Kimura, Takako</creator><creator>Kawase, Yumi</creator><creator>Nara, Futoshi</creator><creator>Kagari, Takashi</creator><creator>Shimozato, Takaichi</creator><creator>Yahara, Chizuko</creator><creator>Inaba, Shinichi</creator><creator>Honda, Tomohiro</creator><creator>Izumi, Takashi</creator><creator>Tamura, Masakazu</creator><creator>Nishi, Takahide</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20140801</creationdate><title>Synthesis and SAR studies of benzyl ether derivatives as potent orally active S1P1 agonists</title><author>Tsuji, Takashi ; 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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 (30mg/kg, p.o.) in rats.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>24909680</pmid><doi>10.1016/j.bmc.2014.05.035</doi><tpages>11</tpages></addata></record> |
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| identifier | ISSN: 0968-0896 |
| ispartof | Bioorganic & medicinal chemistry, 2014-08, Vol.22 (15), p.4246-4256 |
| issn | 0968-0896 1464-3391 |
| language | eng |
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| subjects | Administration, Oral Animals Binding Sites Bradycardia Ethers - chemistry Ethers - pharmacokinetics Ethers - therapeutic use Graft Rejection - prevention & control Half-Life Heart Rate - drug effects HvGR Immunosuppressive Agents - chemistry Immunosuppressive Agents - pharmacology Immunosuppressive Agents - therapeutic use Lymphocyte Male Modeling Molecular Docking Simulation Protein Structure, Tertiary Rats Rats, Inbred Lew Receptors, Lysosphingolipid - agonists Receptors, Lysosphingolipid - metabolism S1P1 receptor agonist Structure-Activity Relationship Transplantation, Homologous |
| title | Synthesis and SAR studies of benzyl ether derivatives as potent orally active S1P1 agonists |
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