Stereochemistry-activity relationship of orally active tetralin S1P agonist prodrugs.
Modifying FTY720, an immunosuppressant modulator, led to a new series of well phosphorylated tetralin analogs as potent S1P1 receptor agonists. The stereochemistry effect of tetralin ring was probed, and (-)-(R)-2-amino-2-((S)-6-octyl-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol was identified as a good SphK2 substrate and potent S1P1 agonist with good oral bioavailability.
Ma
Bin
B
BiogenIdec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA. bin.ma@biogenidec.com
Guckian
Kevin M
KM
Lin
Edward Yin-Shiang
EY
Lee
Wen-Cherng
WC
Scott
Daniel
D
Kumaravel
Gnanasambandam
G
Macdonald
Timothy L
TL
Lynch
Kevin R
KR
Black
Cheryl
C
Chollate
Sowmya
S
Hahm
Kyungmin
K
Hetu
Gregg
G
Jin
Ping
P
Luo
Yi
Y
Rohde
Ellen
E
Rossomando
Anthony
A
Scannevin
Robert
R
Wang
Joy
J
Yang
Chunhua
C
D000284:Administration, Oral; D000818:Animals; D018360:Crystallography, X-Ray; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D008231:Lymphopenia / Q000139:chemically induced; D051379:Mice; D008958:Models, Molecular; D009103:Multiple Sclerosis / Q000188:drug therapy; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000099157:Sphingosine Kinase
D007166:Immunosuppressive Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); D011355:Prodrugs; D049349:Receptors, Lysosphingolipid; D013764:Tetrahydronaphthalenes; D000099157:Sphingosine Kinase; C095210:tetralin