Design and synthesis of conformationally constrained 3-( N-alkylamino)propylphosphonic acids as potent agonists of sphingosine-1-phosphate (S1P) receptors

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 19; pp. 4861 - 4866
• Main Authors: Yan, Lin, Hale, Jeffrey J., Lynch, Christopher L., Budhu, Richard, Gentry, Amy, Mills, Sander G., Hajdu, Richard, Keohane, Carol Ann, Rosenbach, Mark J., Milligan, James A., Shei, Gan-Ju, Chrebet, Gary, Bergstrom, James, Card, Deborah, Rosen, Hugh, Mandala, Suzanne M.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 04.10.2004; Elsevier
• Subjects: Animals; Biological and medical sciences; CHO Cells; Cricetinae; Drug Design; Humans; Medical sciences; Miscellaneous; Molecular Conformation; Organophosphonates - chemical synthesis; Organophosphonates - chemistry; Organophosphonates - pharmacology; Pharmacology. Drug treatments; Receptors, Lysosphingolipid - agonists; Structure-Activity Relationship; Molecular rigidity; Agonist; Cyclohexane derivatives; Intravenous administration; Rodentia; Phosphonic acids; Steric hindrance; Biological activity; Phosphorus Organic compounds; Pyrrolidine derivatives; Vertebrata; Mammalia; Mouse; Animal; Chemical synthesis; Lymphocyte
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.07.049

A series of conformationally constrained analogs of 3 were synthesized and evaluated as S1P receptor agonists. Several novel scaffolds were identified as suitable for further investigation. A series of conformationally constrained 3-( N-alkylamino)propylphosphonic acids were systematically synthesized and their activities as S1P receptor agonists were evaluated. Several pyrrolidine and cyclohexane analogs had S1P receptor profiles comparable to the acyclic lead compound, 3-( N-tetradecylamino)propylphosphonic acid ( 3), lowered circulating lymphocytes in mice after iv administration and were thus identified as being suitable for further investigations.