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
Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
New Modality Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Bioorg Med Chem. 2014 Aug 1;22(15):4246-56. doi: 10.1016/j.bmc.2014.05.035. Epub 2014 May 24.
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.
我们在此报告了一系列作为S1P₁受体调节剂的苄基醚化合物的合成及构效关系（SAR）。通过我们的SAR研究发现，在2a的中心苯环上引入取代基会显著影响S1P₁和S1P₃激动活性，特别是2位上的乙基具有令人满意的S1P₁/S1P₃选择性。利用S1P₁ X射线晶体结构和S1P₃同源性建模进行的对接研究合理地解释了2位取代基变化引起的S1P₁和S1P₃激动活性的这些变化。我们发现化合物2b和2e具有强大的体内免疫抑制功效以及可接受的S1P₁/S1P₃选择性，并通过在大鼠口服化合物（30 mg/kg，口服）后评估心率变化，证实这些化合物的体内心动过缓风险较低。
