title: Synthesis and SAR studies of benzyl ether derivatives as potent orally active S1P₁ agonists.
abstract: 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.
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsuji
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Goto
authors.affiliation: New Modality Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Sekiguchi
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Takemoto
authors.affiliation: New Drug Regulatory Affairs Department, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Mizuno
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kawase
authors.affiliation: Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Nara
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kagari
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takaichi
authors.initials: T
authors.lastname: Shimozato
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Chizuko
authors.initials: C
authors.lastname: Yahara
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Inaba
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Honda
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
authors.affiliation: Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Tamura
authors.affiliation: Daiichi Sankyo India Pharma Pvt. Ltd, Village Sarhaul, Sector 18, Udyog Vihar Industrial Area, Gurgaon 122015, Haryana, India. Electronic address: takahide.nishi.wd@dsin.co.in.
authors.forename: Takahide
authors.initials: T
authors.lastname: Nishi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D004987:Ethers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006084:Graft Rejection / Q000517:prevention & control; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D051381:Rats; D011917:Rats, Inbred Lew; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014184:Transplantation, Homologous
chemical_list: D004987:Ethers; D007166:Immunosuppressive Agents; D049349:Receptors, Lysosphingolipid
keywords: Bradycardia; HvGR; Lymphocyte; Modeling; S1P(1) receptor agonist