Letters
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 27 6665
Cottens, S.; Hof, R.; Bruns, C.; Prieschl, E.; Baumruker, T.;
Hiestand, P.; Foster, C. A.; Zollinger, M.; Lynch, K. R. The
Immune Modulator FTY720 Targets Sphingosine-1-Phosphate
Receptors. J. Biol. Chem. 2002, 277, 21453-21457.
(2) Hale, J. J.; Neway, W.; Mills, S. G.; Hajdu, R.; Keohane, C. A.;
Rosenbach, M.; Milligan, J.; Shei, G.-J.; Chrebet, G.; Bergstrom,
J.; Card, D.; Koo, G. C.; Koprak, S. L.; Jackson, J. J.; Rosen, H.;
Mandala, S. Potent S1P Receptor Agonists Replicate the Phar-
macologic Actions of the Novel Immune Modulator FTY720.
Bioorg. Med. Chem. Lett. 2004, 14, 3351-3355. (b) Hale, J. J.;
Doherty, G.; Toth, L.; Li, Z.; Mills, S. G.; Hajdu, R.; Keohane, C.
A.; Rosenbach, M.; Milligan, J.; Shei, G.-J.; Chrebet, G.; Berg-
strom, J.; Card, D.; Rosen, H.; Mandala, S. The Discovery of 3-(N-
Alkyl)aminopropylphosphonic acids as Potent S1P Receptor
Agonists. Bioorg. Med. Chem. Lett. 2004, 14, 3495-3499. (c)
Hale, J. J.; Doherty, G.; Toth, L.; Mills, S. G.; Hajdu, R.;
Keohane, C. A.; Rosenbach, M.; Milligan, J.; Shei, G.-J.; Chrebet,
G.; Bergstrom, J.; Card, D.; Forrest, M.; Sun, S.-Y.; West, S.;
Xie, H.; Nomura, N.; Rosen, H.; Mandala, S. Selecting Against
S1P3 Enhances the Acute Cardiovascular Tolerability of S1P
Receptor Agonists. Bioorg. Med. Chem. Lett. 2004, 14, 3501-
3505.
Figure 2. PBL counts vs compound plasma concentration
(nM) in femoral artery cannulated Lewis rats (n ) 3) after a
single 3 mpk po dose of 18.
(3) Chiba, K.; Yanagawa, Y.; Masubuchi, Y.; Kataoka, H.; Kawagu-
chi, T.; Ohtsuki, M.; Hoshino, Y. FTY720, a Novel Immunosup-
pressant, Induces Sequestration of Circulating Mature Lym-
phocytes by Acceleration of Lymphocyte Homing in Rats. I.
FTY720 Selectively Decreases the Number of Circulating Mature
Lymphocytes by Acceleration of Lymphocyte Homing. J. Immu-
nol. 1998, 160, 5037-5044.
likelihood that S1P1 agonist-induced alterations to
lymphocyte trafficking are driven and maintained by
trough, not peak, plasma compound concentrations.
In conclusion, the incorporation of the structures of
moderately potent, selective S1P1 receptor agonists
identified from high-throughput screening into an exist-
ing lead series S1P1 agonists has been found to provide
potent S1P1 agonists that select against the S1P2, S1P3,
and S1P4 receptor subtypes. Initial investigations have
shown that the systemic administration of 1-benzyl-3-
carboxyazetidine analogues such as 18 and 24 induce a
lowering of circulating lymphocytes in rodents similarly
to 1, and that these new analogues have excellent cross-
species pharmacokinetic profiles. The further optimiza-
tion of the S1P1 receptor agonists described herein as
well as details of the pharmacology and immunosup-
pressive efficacy of these compounds will be the subject
of future reports.
(4) Anliker, B.; Chun, J. Cell Surface Receptors in Lysophospholipid
Signaling. Sem. Cell. Dev. Biol. 2004, 15, 457-465.
(5) Matloubian, M.; Lo, C. G.; Cinamon, G.; Lesneski, M. J.; Xu, Y.;
Brinkmann, V.; Allende, M. L.; Proia, R. L.; Cyster, J. G.
Lymphocyte Egress from Thymus and Peripheral Lymphoid
Organs is Dependent on S1P Receptor 1. Nature 2004, 427, 355-
360. (b) Allende, M. L.; Dreier, J. L.; Mandala, S.; Proia, R. L.
Expression of the Sphingosine-1-Phosphate, S1P1, on T-cells
Controls Thymic Emigration. J. Biol. Chem. 2004, 279, 15396-
15401.
(6) Budde, K.; Schmouder, R. L.; Brunkhorst, R.; Nashan, B.;
Lu¨cker, P. W.; Mayer, T.; Choudhury, S.; Skerjanec, A.; Kraus,
G.; Neumayer, H. H. First Human Trial of FTY720, a Novel
Immunomodulator, in Stable Renal Transplant Patients. J. Am.
Soc. Nephrol. 2002, 13, 1073-1083.
(7) Sanna, M. G.; Liao, J.; Jo, E.; Alfonso, C.; Ahn, M.-Y.; Peterson,
M. S.; Webb, B.; Lefebvre, S.; Chun, J.; Rosen, H. Sphingosine-
1-Phosphate (S1P) Receptor Subtypes S1P1 and S1P3, Respec-
tively, Regulate Lymphocyte Recirculation and Heart Rate. J.
Biol. Chem. 2004, 279, 13839-13848. (b) Forrest, M.; Sun, S.-
Y.; Hajdu, R.; Bergstrom, J.; Card, D.; Doherty, G.; Hale, J.;
Keohane, C.; Meyers, C.; Milligan, J.; Mills, S.; Nomura, N.;
Rosen, H.; Rosenbach, M.; Shei-G.-J.; Singer, I. I.; Tian, M.;
West, S.; White, V.; Xie, J.; Proia, R. L.; Mandala, S. Immune
Cell Regulation and Cardiovascular Effects of Sphingosine-1-
Phosphate Receptor Agonists in Rodents Are Mediated via
Distinct Receptor Subtypes. J. Pharmacol. Exp. Ther. 2004, 309,
758-768.
(8) Yan, L.; Hale, J. J.; Lynch, C. L.; Budhu, R.; Gentry, A.; Mills,
S. G.; Hajdu, R.; Keohane, C. A.; Rosenbach, M. J.; Milligan, J.
A.; Shei, G.-J.; Chrebet, G.; Bergstrom, J.; Card, D.; Rosen, H.;
Mandala, S. M. Design and Synthesis of Conformationally
Constrained 3-(N-Alkylamino)propylphosphonic acids as Potent
Agonists of Sphingosine-1-Phosphate (S1P) Receptors. Bioorg.
Med. Chem. Lett. 2004, 14, 4861-4866.
Acknowledgment. The authors thank Larry Col-
well, William Feeney, and Susan Iliff for coordinating
the PK experiments (Table 3) in the rat, dog, and
monkey, respectively, and Charlotte Trainor for con-
ducting cbc determinations in the dog and monkey
experiments.
Supporting Information Available: Experimental pro-
cedures and characterization data for 15, 18, 22, and 24,
ligand-induced [35S]-GTPγS S1P1 binding for the compounds
in Table 2, 24 h PBL lowering dose-response data for 18 in
the rat, and data used to generate Figure 2. This material is
(9) Parrill, A. L.; Wang, D.; Bautista, D. L.; Van Brocklyn, J. R.;
Lorincz, Z.; Fischer, D. J.; Baker, D. L.; Liliom, K.; Spiegel, S.;
Tigyi, G. Identification of Edg1 Receptor Residues That Recog-
nize Sphingosine-1-Phosphate. J. Biol. Chem. 2000, 275, 39379-
39384.
(10) Ferrer, M.; Kolodin, G. D.; Zuck, P.; Peltier, R.; Berry, K.;
Mandala, S. M.; Rosen, H.; Ota, H.; Ozaki, S.; Inglese, J.;
References
A Fully Automated [
35S]GTPγS Scintillation
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