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
  • 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: [email protected].
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.