Journal of Medicinal Chemistry
ARTICLE
1H), 5.54 (br s, 2H), 5.01 (spt, J = 6.1 Hz, 1H), 4.78 (dd, J = 15.8, 8.3 Hz,
1H), 4.62 (d, J = 15.8 Hz, 1H), 4.01ꢀ3.90 (m, 5H), 3.65ꢀ3.55 (m, 1H),
3.47ꢀ3.43 (m, 1H), 3.28ꢀ3.19 (m, 1H), 3.18ꢀ3.09 (m, 1H), 2.50 (s,
3H), 1.42 (d, J = 6.1 Hz, 6H). 13C NMR (DMSO-d6) δ ppm 173.0,
169.0, 162.5, 136.0, 134.5, 133.7, 132.1, 131.9, 128.0, 125.2, 124.6, 115.9,
115.2, 114.9, 102.4, 72.5, 66.6, 56.9, 56.7, 50.7, 47.4, 23.9, 21.4, 16.2.
HRMS calculated for C25H29N4O4: 449.2189. Found: 449.2194.
(6) 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.
(7) Sanna, M. G.; Liao, J.; Jo, E.; Alfonso, C.; Ahn, M.-Y.; Peterson,
M. S.; Webb, B.; Lefebvre, S.; Chun, J.; Gray, N.; Rosen, H. Sphingosine
1-Phosphate (S1P) Receptor Subtypes S1P1 and S1P3, Respectively,
Regulate Lymphocyte Recirculation and Heart Rate. J. Biol. Chem. 2004,
279, 13839–13848.
(8) Gergely, P.; Wallstr€om, E.; Nuesslein-Hildesheim, B.; Bruns, C.;
Zꢀecri, F.; Cooke, N.; Traebert, M.; Tuntland, T.; Rosenberg, M.;
Saltzman, M. Phase I study with selective S1P1/S1P5 receptor modulator
BAF312 indicates that S1P1 rather than S1P3 mediates transient heart
rate reduction in humans. Mult. Scler. 2009, 15, S31–S150.
(9) Meno-Tetang, G. M. L.; Li, H.; Mis, S.; Pyszczynski, N.; Heining,
P.; Lowe, P.; Jusko, W. J. Physiologically based pharmacokinetic
modeling of FTY720 (2-amino-2[2-(-4-octylphenyl)ethyl]propane-
1,3-diol hydrochloride) in rats after oral and intravenous doses. Drug
Metab. Dispos. 2006, 34, 1480–1487.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures for
b
the synthesis of compounds 9ꢀ14, in vitro assay protocols for
the determination of EC50, and protocols for in vivo studies and
data correlations. This material is available free of charge via the
’ AUTHOR INFORMATION
Corresponding Author
*Telephone: + 44 1438 764319. Fax: + 44 1438 768302. E-mail:
(10) Brinkmann, V. FTY720 (fingolimod) in Multiple Sclerosis:
therapeutic effects in the immune and the central nervous system. Br. J.
Pharmacol. 2009, 158, 1173–1182.
(11) Noguchi, K.; Chun, J. Roles for lysophospholipid S1P receptors
in multiple sclerosis. Crit. Rev. Biochem. Mol. Biol. 2011, 46, 2–10.
(12) Buzard, D. J.; Thatte, J.; Lerner, M.; Edwards, J.; Jones, R. M.
Recent Progress in the Development of Selective S1P1 Receptor
Agonists for the Treatment of Inflammatory and Autoimmune disor-
ders. Expert Opin. Ther. Pat. 2008, 18, 1141–1159.
(13) Nishi, T.; Miyazaki, S.; Takemoto, T.; Suzuki, K.; Iio, Y.;
Nakajima, K.; Ohnuki, T.; Kawase, Y.; Nara, F.; Inaba, S.; Izumi, T.;
Yuita, H.; Oshima, K.; Doi, H.; Inoue, R.; Tomisato, W.; Kagari, T.;
Shimozato, T. Discovery of CS-0777: A Potent, Selective, and Orally
Active S1P1 Agonist. ACS Med. Chem. Lett. 2011, 2, 368–372.
(14) Bolli, M. H.; Abele, S.; Binkert, C.; Bravo, R.; Buchmann, S.;
Bur, D.; Gatfield, J.; Hess, P.; Kohl, C.; Mangold, C.; Mathys, B.;
Menyhart, K.; M€uller, C.; Nayler, O.; Scherz, M.; Schmidt, G.; Sippel, V.;
Steiner, B.; Strasser, D.; Treiber, A.; Weller, T. 2-Imino-thiazolidin-4-
one Derivatives as Potent, Orally Active S1P1 Receptor Agonists. J. Med.
Chem. 2010, 53, 4198–4211.
(15) Cee, V. J.; Frohn, M.; Lanman, B. A.; Golden, J.; Muller, K.;
Neira, S.; Pickrell, A.; Arnett, H.; Buys, J.; Gore, A.; Fiorino, M.; Horner,
M.; Itano, A.; Lee, M. R.; McElvain, M.; Middleton, S.; Schrag, M.;
Rivenzon-Segal, D.; Vargas, H. M.; Xu, H.; Xu, Y.; Zang, X.; Siu, J.;
Wong, M.; B€urli, R. W. Discovery of AMG 369, a Thiazolo[5,4-
b]pyridine Agonist of S1P1 and S1P5. ACS Med. Chem. Lett. 2011,
2, 107–112.
(16) Walker, J. K. Discovery of a potent and selective S1P1 receptor
agonist for the treatment of rheumatoid arthritis. ACS meeting, 21ꢀ25
March, 2010, San Francisco, CA.
(17) Demont, E. H.; Andrews, B. I.; Bit, R. A.; Campbell, C. A.;
Cooke, J. W. B.; Deeks, N.; Desai, S.; Dowell, S. J.; Gaskin, P.; Gray,
J. R. J.; Haynes, A.; Holmes, D. S.; Kumar, U.; Morse, M. A.; Osborne,
G. J.; Panchal, T.; Patel, B.; Perboni, A.; Taylor, S.; Watson, R.;
Witherington, J.; Willis, R. Discovery of a selective S1P1 receptor agonist
efficacious at low oral dose and devoid of effects on heart rate. ACS Med
Chem. Lett. 2011, 2, 444–449.
(18) Didziapetris, R.; Japertas, P.; Avdeef, A.; Petrauskas, A. Classi-
fication Analysis of P-Glycoprotein Substrate Specificity. J. Drug Target-
ing 2003, 11, 391–406.
(19) Such a selectivity profile has already been reported with this
biaryl oxadiazole template. See: Li, Z.; Chen, W.; Hale, J. J.; Lynch, C. L.;
Mills, S. G.; Hajdu, R.; Keohane, C. A.; Rosenbach, M. J.; Milligan, J. A.;
Shei, G.-J.; Chrebet, G.; Parent, S. A.; Bergstrom, J.; Card, D.; Forrest,
M.; Quackenbush, E. J.; Wickham, L. A.; Vargas, H.; Evans, R. M.; Rosen,
H.; Mandala, S. Discovery of Potent 3,5-Diphenyl-1,2,4-oxadiazole
’ ACKNOWLEDGMENT
The authors thank Dr. Richard Upton and Mr. Nick Waite for
NMR support, Dr. Bill Leavens for recording HRMS spectra,
Mrs. Helen Tracey for conducting P-gp and permeability experi-
ments, Mrs. Catherine Cartwright and Miss Aarti Patel for
determining intrinsic clearance, and Mrs. Karen Leavens for
supporting the lymphopenia studies. Mrs. Shenaz Nunhuck and
Mr. Alan Hill are also acknowledged for pKa and CHI determina-
tion, and Miss Helen Garden for solubility measurements.
’ ABBREVIATIONS
RRMS, remitting relapsing multiple sclerosis; CNS, central ner-
vous system; BBB, blood-brain barrier; PSA, polar surface area;
CHI, chromatographic hydrophobicity index; CAD, cationic
amphiphilic drug; LiHMDS, lithium bis(trimethylsilyl)amide;
TMSCl, chloro(trimethyl)silane; DIAD, diisopropyl diazene-
1,2-dicarboxylate; GPCR, G-protein-coupled receptor
’ REFERENCES
(1) Martini, S.; Peters, H.; B€ohler, T.; Budde, K. Current Perspec-
tives on FTY720. Expert Opin. Invest. Drugs 2007, 16, 505–518.
(2) Billich, A.; Bornancin, F.; Dꢀevay, P.; Mechtcheriakova, D.; Urtz, N.;
Baumruker, T. Phosphorylation of the Immunomodulatory Drug FTY720
by Sphingosine Kinases. J. Biol. Chem. 2003, 278, 47408–47415.
(3) Albert, R.; Hinterding, K.; Brinkmann, V.; Guerini, D.; M€uller-
Hartwieg, C.; Knecht, H.; Simeon, C.; Streiff, M.; Wagner, T.; Welzenbach,
K.; Zꢀecri, F.; Zollinger, M.; Cooke, N.; Francotte, E. Novel Immunomo-
dulator FTY720 Is Phosphorylated in Rats and Humans to Form a Single
Stereoisomer. Identification, Chemical Proof, and Biological Characterisa-
tion of the Biologically Active Species and Its Enantiomer. J. Med. Chem.
2005, 48, 5373–5377.
(4) 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.
(5) Wei, S. H.; Rosen, H.; Matheu, M. P.; Sanna, M. G.; Wang, S.-K.;
Jo, E.; Wong, C.-H.; Parker, I.; Cahalan, M. D. Sphingosine 1-Phosphate
Type 1 receptor Agonism Inhibits Transendothelial Migration of Medul-
lary T Cells to Lymphatic Sinuses. Nat. Immunol. 2005, 6, 1228–1235.
6732
dx.doi.org/10.1021/jm200609t |J. Med. Chem. 2011, 54, 6724–6733