872710-09-3Relevant academic research and scientific papers
Discovery of a 1-Methyl-3,4-dihydronaphthalene-Based Sphingosine-1-Phosphate (S1P) Receptor Agonist Ceralifimod (ONO-4641). A S1P1 and S1P5 Selective Agonist for the Treatment of Autoimmune Diseases
Kurata, Haruto,Kusumi, Kensuke,Otsuki, Kazuhiro,Suzuki, Ryo,Kurono, Masakuni,Komiya, Takaki,Hagiya, Hiroshi,Mizuno, Hirotaka,Shioya, Hiroki,Ono, Takeji,Takada, Yuka,Maeda, Tatsuo,Matsunaga, Norikazu,Kondo, Tetsu,Tominaga, Sachiko,Nunoya, Ken-Ici,Kiyoshi, Hidekazu,Komeno, Masaharu,Nakade, Shinji,Habashita, Hiromu
, p. 9508 - 9530 (2017/12/26)
The discovery of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid 13n (ceralifimod, ONO-4641), a sphingosine-1-phosphate (S1P) receptor agonist selective for S1P1 and S1P5, is described. While it has been revealed that the modulation of the S1P1 receptor is an effective way to treat autoimmune diseases such as relapsing-remitting multiple sclerosis (RRMS), it was also reported that activation of the S1P3 receptor is implicated in some undesirable effects. We carried out a structure-activity relationship (SAR) study of hit compound 6 with an amino acid moiety in the hydrophilic head region. Following identification of a lead compound with a dihydronaphthalene central core by inducing conformational constraint, optimization of the lipophilic tail region led to the discovery of 13n as a clinical candidate that exhibited >30 000-fold selectivity for S1P1 over S1P3 and was potent in a peripheral lymphocyte lowering (PLL) test in mice (ED50 = 0.029 mg/kg, 24 h after oral dosing).
COMPOUND HAVING S1P RECEPTOR BINDING POTENCY AND USE THEREOF
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Provided are: a compound represented by formula (I): (wherein ring A and ring D each represent a cyclic group which may have a substituent(s); E and G each represent a bond or a spacer having 1 to 8 atoms in its main chain; L represents a hydrogen atom or a substituent; X represents amino which may have a substituent(s), or a heterocylcic group which contains at least one nitrogen atom and which may have a substituent(s); n represents 0 to 3, in which when n is 2 or more, a plurality of ring A's may be the same or different from one another); a salt thereof; an N-oxide form thereof; a solvate thereof; a prodrug thereof; and a medicament which includes those. The compound represented by formula (I) is capable of binding S1P receptors (in particular, EDG-1 and/or EDG-6), and useful for preventing and/or treating rejection in transplantation, autoimmune diseases, allergic diseases, etc.
