Synthesis and SAR of 1,3-thiazolyl thiophene and pyridine derivatives as potent, orally active and S1P₃-sparing S1P₁ agonists

Autor: Masayoshi, Asano, Tsuyoshi, Nakamura, Yukiko, Sekiguchi, Yumiko, Mizuno, Takahiro, Yamaguchi, Kazuhiko, Tamaki, Takaichi, Shimozato, Hiromi, Doi-Komuro, Takashi, Kagari, Wataru, Tomisato, Ryotaku, Inoue, Hiroshi, Yuita, Keiko, Oguchi-Oshima, Reina, Kaneko, Futoshi, Nara, Yumi, Kawase, Noriko, Masubuchi, Shintaro, Nakayama, Tetsufumi, Koga, Eiko, Namba, Hatsumi, Nasu, Takahide, Nishi
Rok vydání: 2012
Předmět:
Zdroj: Bioorganicmedicinal chemistry letters. 22(9)
ISSN: 1464-3405
Popis: We have previously disclosed 1,2,4-oxadiazole derivative 3 as a potent S1P(3)-sparing S1P(1) agonist. Although compound 3 exhibits potent and manageable immunosuppressive efficacy in various in vivo models, recent studies have revealed that its 1,2,4-oxadiazole ring is subjected to enterobacterial decomposition. As provisions for unpredictable issues, a series of alternative compounds were synthesized on the basis of compound 3. Extensive SAR studies led to the finding of 1,3-thiazole 24c with the EC(50) value of 3.4 nM for human S1P(1), and over 5800-fold selectivity against S1P(3). In rat on host versus graft reaction (HvGR), the ID(50) value of 24c was determined at 0.07 mg/kg. The pharmacokinetics in rat and monkey is also reported. Compared to compound 3, 24c showed excellent stability against enterobacteria.
Databáze: OpenAIRE
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