Design and synthesis of conformationally constrained 3-(N-alkylamino)propylphosphonic acids as potent agonists of sphingosine-1-phosphate (S1P) receptors.
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.
Yan
Lin
L
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. lin_yan@merck.com
Hale
Jeffrey J
JJ
Lynch
Christopher L
CL
Budhu
Richard
R
Gentry
Amy
A
Mills
Sander G
SG
Hajdu
Richard
R
Keohane
Carol Ann
CA
Rosenbach
Mark J
MJ
Milligan
James A
JA
Shei
Gan-Ju
GJ
Chrebet
Gary
G
Bergstrom
James
J
Card
Deborah
D
Rosen
Hugh
H
Mandala
Suzanne M
SM
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D015195:Drug Design; D006801:Humans; D008968:Molecular Conformation; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship
D063065:Organophosphonates; D049349:Receptors, Lysosphingolipid