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

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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Tsuji T,Suzuki K,Nakamura T,Goto T,Sekiguchi Y,Ikeda T,Fukuda T,Takemoto T,Mizuno Y,Kimura T,Kawase Y,Nara F,Kagari T,Shimozato T,Yahara C,Inaba S,Honda T,Izumi T,Tamura M,Nishi T

doi

10.1016/j.bmc.2014.05.035

subject

Has Abstract

pub_date

2014-08-01 00:00:00

pages

4246-56

issue

15

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(14)00384-8

journal_volume

22

pub_type

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