Synthesis, stereochemical determination and biochemical characterization of the enantiomeric phosphate esters of the novel immunosuppressive agent FTY720.
The novel immunosuppressive agent FTY720 (1) is phosphorylated in vivo in a variety of species yielding an active metabolite that is an agonist of four of the five known G-protein-coupled sphingosine-1-phosphate (S1P) receptors. A synthesis amenable to producing gram quantities of the stereoisomeric phosphate esters, a determination of their absolute stereochemistry via an enantioselective synthesis and their characterization as S1P receptor agonists and antagonists is reported.
Hale
Jeffrey J
JJ
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. jeffrey_hale@merck.com
Yan
Lin
L
Neway
William E
WE
Hajdu
Richard
R
Bergstrom
James D
JD
Milligan
James A
JA
Shei
Gan-Ju
GJ
Chrebet
Gary L
GL
Thornton
Rosemary A
RA
Card
Deborah
D
Rosenbach
Mark
M
HughRosen
Mandala
Suzanne
S
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis*; D008968:Molecular Conformation; D010755:Organophosphates / Q000138:chemical synthesis*; D011409:Propylene Glycols / Q000138:chemical synthesis*; D013110:Sphingosine / Q000031:analogs & derivatives
D007166:Immunosuppressive Agents; D010755:Organophosphates; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine