Synthesis and SAR studies of a novel class of S1P1 receptor antagonists.
A series of Sodium 4-[(4-butoxyphenyl)thio]-2'-substituted-1,1'-biphenyl-3- sulfonates were identified as functional sphingosine-1-phosphate (S1P) antagonists with selectivity for the S1P(1) receptor subtype starting from chemical lead 2, which was found while screening our in-house compound library. We performed chemical modifications on each regional structure of compound 2, for example, on the three ring compartments, the benzyl substituents, and the long alkyl chain part. The introduction of a biphenyl skeletal structure and the installation of a hydroxyl group onto the terminal carbon in the side-chain region resulted in the potent derivative 35c, which showed >500-fold more potent S1P(1) inhibitory activity than lead compound 2. We report herein the synthesis and structure-activity relationships of structurally novel S1P(1) receptor antagonists.
Nakamura
Tsuyoshi
T
Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd, 1-2-58 Hiromachi, Tokyo 140-8710, Japan.
Yonesu
Kiyoaki
K
Mizuno
Yumiko
Y
Suzuki
Chie
C
Sakata
Yuki
Y
Takuwa
Yoh
Y
Nara
Futoshi
F
Satoh
Susumu
S
D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D008246:Lysophospholipids / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*
D001713:Biphenyl Compounds; D007202:Indicators and Reagents; D008246:Lysophospholipids; D013451:Sulfonic Acids; C060506:sphingosine 1-phosphate; D000242:Cyclic AMP; D013110:Sphingosine