Journal of Medicinal Chemistry p. 9508 - 9530 (2017)
Update date:2022-08-15
Topics:
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
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).
View Morewebsite:http://www.afinechem.com
Contact:+86-571-85134551
Address:No. 206 Zhen Hua Road, Hangzhou 310030, Zhejiang, China
Naturalin Bio-Resource Co., Ltd
website:http://www.naturalin.com
Contact:+86-0731-84430651
Address:B1-402, Lu-Valley Enterprise Square.No.27 Wenxuan Road. Lu-Valley Hi-Tech District.
Taizhou Chenyi chemical co. LTD,
Contact:13736652831
Address:NO.273 SHANGHAI SOUTH STREET,LUQIAO DISTRICT,ZHEJIANG PROVINCE,CHINA.
SHANGHAI SYSTEAM BIOCHEM CO., LTD
website:http://www.systeambc.com
Contact:86-021-58380978
Address:Building 87,Lane 669, Dong Jing Road Shanghai,P.R.China
LinHai Cina Chemical Co., LTD.
Contact:0576-85580989
Address:Pharma-chem zone,Duqiao,Linhai,Zhejiang,China
Doi:10.1021/jo01271a093
(1968)Doi:10.1016/0040-4020(95)00475-N
(1995)Doi:10.1016/0022-328X(95)05392-3
(1995)Doi:10.1248/cpb.47.1237
(1999)Doi:10.1021/ic50216a031
(1981)Doi:10.1016/0040-4020(94)01016-S
(1995)