827345-02-8Relevant articles and documents
Synthesis and SAR studies of benzyl ether derivatives as potent orally active S1P1 agonists
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
, p. 4246 - 4256 (2014)
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 S1P 3 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 S1P 1/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.
Kinase-independent phosphoramidate S1P1receptor agonist benzyl ether derivatives
James, Edward,Pertusati, Fabrizio,Brancale, Andrea,McGuigan, Chris
, p. 1371 - 1378 (2017/03/08)
Previously published S1P receptor modulator benzyl ether derivatives have shown potential as being viable therapeutics for the treatment of neurodegenerative diseases, however, two of the most S1P1-selective compounds are reported as being poorly phosphorylated by kinases in vivo. Phosphoramidates of BED compounds (2a, 2b) were synthesised with the aim of producing kinase-independent S1P receptor modulators. Carboxypeptidase, human serum and cell lysate processing experiments were conducted. ProTide BED analogues were found to have an acceptable level of stability in acidic and basic conditions and in vitro metabolic processing experiments showed that they are processed to the desired pharmacologically active monophosphate. The research describes the development of an entirely novel family of therapeutic agents.
