2. Academic Validation
  3. Synthesis and SAR studies of benzyl ether derivatives as potent orally active S1P₁ agonists

Synthesis and SAR studies of benzyl ether derivatives as potent orally active S1P₁ agonists

  • Bioorg Med Chem. 2014 Aug 1;22(15):4246-56. doi: 10.1016/j.bmc.2014.05.035.
Takashi Tsuji 1,  Keisuke Suzuki 1,  Tsuyoshi Nakamura 1,  Taiji Goto 1,  Yukiko Sekiguchi 2,  Takuya Ikeda 1,  Takeshi Fukuda 1,  Toshiyasu Takemoto 1,  Yumiko Mizuno 3,  Takako Kimura 1,  Yumi Kawase 4,  Futoshi Nara 4,  Takashi Kagari 5,  Takaichi Shimozato 5,  Chizuko Yahara 6,  Shinichi Inaba 6,  Tomohiro Honda 6,  Takashi Izumi 6,  Masakazu Tamura 7,  Takahide Nishi 8
Affiliations

Affiliations

  • 1 Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 2 New Modality Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 3 New Drug Regulatory Affairs Department, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 4 Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 5 Frontier Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 6 Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 7 Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 8 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.
PMID: 24909680 DOI: 10.1016/j.bmc.2014.05.035
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.

Keywords

Bradycardia; HvGR; Lymphocyte; Modeling; S1P(1) receptor agonist.

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