Stereochemistry–activity relationship of orally active tetralin S1P agonist prodrugs

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 7; pp. 2264 - 2269
• Main Authors: Ma, Bin, Guckian, Kevin M., Lin, Edward Yin-Shiang, Lee, Wen-Cherng, Scott, Daniel, Kumaravel, Gnanasambandam, Macdonald, Timothy L., Lynch, Kevin R., Black, Cheryl, Chollate, Sowmya, Hahm, Kyungmin, Hetu, Gregg, Jin, Ping, Luo, Yi, Rohde, Ellen, Rossomando, Anthony, Scannevin, Robert, Wang, Joy, Yang, Chunhua
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.04.2010; Elsevier
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Crystallography, X-Ray; FTY720; Immunomodulators; Immunosuppressive Agents - chemistry; Immunosuppressive Agents - metabolism; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - pharmacology; Lymphopenia - chemically induced; Medical sciences; Mice; Models, Molecular; Multiple sclerosis; Multiple Sclerosis - drug therapy; Pharmacology. Drug treatments; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Prodrug; Prodrugs - chemistry; Prodrugs - metabolism; Prodrugs - pharmacokinetics; Prodrugs - pharmacology; Receptors, Lysosphingolipid - agonists; Receptors, Lysosphingolipid - metabolism; S1P; SphK2; Structure-Activity Relationship; Tetrahydronaphthalenes - chemistry; Tetrahydronaphthalenes - metabolism; Tetrahydronaphthalenes - pharmacokinetics; Tetrahydronaphthalenes - pharmacology; Tetralin; X-ray; Tetralin; Multiple sclerosis; S1P; SphK2; FTY720; Prodrug; X-ray; Agonist; Structure activity relation; Bicyclic compound; Aromatic compound; Chemical synthesis; Aminoalcohol; Fingolimod; Enzyme; Transferases; Rodentia; Oral administration; Sphinganine kinase; Bioavailability; Naphthalene derivatives; In vitro; Immunomodulator; Substrate; In vivo; Vertebrata; Mammalia; Mouse; Animal; Affinity; Immunosuppressive agent; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.02.006

The synthesis, characterization and stereochemistry activity relationship of tetralin S1P agonist prodrugs is reported. (2 R,2′ S)- 5 (ED 50 = 0.1 mg/kg) was identified as a good SphK2 substrate and potent S1P1 agonist with good oral bioavailability. 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.