ACS Medicinal Chemistry Letters
LETTER
a Single Stereoisomer. Identification, Chemical Proof, and Biological
Characterisation of the Biologically Active Species and Its Enantiomer.
J. Med. Chem. 2005, 48, 5373–5377.
Acids as Potent and Selective Agonists of Sphingosine-1-phosphate
Receptor-1 (S1P1) with Enhanced Pharmacokinetics Properties. Bioorg.
Med. Chem. Lett. 2007, 17, 828–831.
(6) 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.
(7) 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
Medullary T Cells to Lymphatic Sinuses. Nature Immunol. 2005,
6, 1228–1235.
(8) 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 3-(N-benzyl)aminopropylphosphonic acid S1P receptor
agonists. Bioorg. Med. Chem. Lett. 2004, 14, 3501–3505.
(18) During the preparation of this manuscript, S1P1 agonists
analogous to 7 have been reported as follows:Lanman, B. A.; Cee,
V. J.; Cheruku, S. R.; Frohn, M.; Golden, J.; Lin, J.; Lobera, M.; Marantz,
Y.; Muller, K. M.; Neira, S. C.; Pickrell, A. J.; Rivenzon-Segal, D.; Schutz,
N.; Sharadendu, A.; Yu, X.; Zhang, Z.; Buys, J.; Fiorino, M.; Gore, A.;
Horner, M.; Itano, A.; McElvain, M.; Middleton, S.; Schrag, M.; Vargas,
H. M.; Xu, H.; Xu, Y.; Zhang, X.; Siu, J.; B€urli, R. W. Discovery of a
Potent S1P3-Sparing Benzothiazole Agonist of Sphingosine-1 Phos-
phate Receptor 1 (S1P1). ACS Med. Chem. Lett. 2011, 2, 102–106.
(19) Saha, A. K.; Yu, X.; Lin, J.; Lobera, M.; Sharadendu, A.;
Chereku, S.; Schutz, N.; Segal, D.; Marantz, Y.; McCauley, D.; Mid-
dleton, S.; Siu, J.; B€urli, R. W.; Buys, J.; Horner, M.; Salyers, K.; Schrag,
M.; Vargas, H. M.; Xu, Y.; McElvain, M.; Xu, H. Benzofuran Derivatives
as Potent, Orally Active S1P1 Receptor Agonists: A Preclinical Lead
Molecule for MS. ACS Med. Chem. Lett. 2011, 2, 97–101.
(9) 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.
(10) 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.
(11) Hamada, M.; Nakamura, M.; Kiuchi, M.; Marukawa, K.;
Tomatsu, A.; Shimano, K.; Sato, N.; Sugahara, K.; Asayama, M.; Takagi,
K.; Adachi, K. Removal of Sphingosine 1-Phosphate receptor-3 (S1P3)
Agonism is Essential, But Inadequate to Obtain Immunomodulating
2-Aminopropane-1,3-diol S1P1 Agonists with Reduced Effect on Heart
Rate. J. Med. Chem. 2010, 53, 3154–3168.
(20) Feigin, V. Irampanel. Curr. Opin. Invest. Drugs. 2002, 3,
908–910.
(21) Hirawat, S.; Welch, E. M.; Elfring, G. L.; Northcutt, V. J.;
Paushkin, S.; Hwang, S.; Leonard, E. M.; Almstead, N. G.; Ju, W.; Peltz,
S. W.; Miller, L. L. Safety, Tolerability, and Pharmacokinetics of
PCT124, a Nonaminoglycoside Nonsense Mutation Suppressor, Fol-
lowing Single- and Multiple-Dose Administration to Healthy Male and
Female Adult Volunteers. J. Clin. Pharmacol. 2007, 47, 430–444.
(22) Leeson, P. D.; Springthorpe, B. The Influence of Drug-like
Concepts on Decision-making in Medicinal Chemistry. Nat. Rev. Drug
Discovery 2007, 6, 881–890.
(23) See, for example:Lipinski, C. A. Lead- and Drug-like Com-
pounds: The Rule-of-five Revolution. Drug Discovery Today Technol.
2004, 1, 337–341.
(24) See also:Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney,
P. J. Experimental and computational approaches to estimate solubility
and permeability in drug discovery and development settings. Adv. Drug
Delivery Rev. 1997, 23, 3–25.
(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. Patents 2008, 18, 1141–1159.
(13) Crosignani, S.; Bombrun, A.; Covini, D.; Maio, M.; Marin, D.;
Quattropani, A.; Swinnen, D.; Simpson, D.; Sauer, W.; Franc-on, B.;
Martin, T.; Cambet, Y.; Nichols, A.; Martinou, I.; Burgat-Charvillon, F.;
Rivron, D.; Donini, C.; Schott, O.; Eligert, V.; Novo-Perez, L.; Vitte,
P.-A.; Arrighi, J.-F. Discovery of a Novel Series of Potent S1P1 Agonists.
Bioorg. Med. Chem. Lett. 2010, 20, 1516–1519.
(14) Shimizu, H.; Takahashi, M.; Kaneko, T.; Murakami, T.;
Hakamata, Y.; Kudou, S.; Kishi, T.; Fukuchi, K.; Iwanami, S.; Kuriyama,
K.; Yasue, T.; Enosawa, S.; Matsumoto, K.; Takeyoshi, I.; Morishita, Y.;
Kobayashi, E. KRP-203, a Novel Synthetic Immunosuppressant, Pro-
longs Graft Survival and Attenuates Chronic Rejection in Rat Skin and
Heart Allografts. Circulation 2005, 111, 222–229.
(25) Wenlock, M. C.; Austin, R. P.; Barton, P.; Davis, A. M.; Leeson,
P. D. A Comparison of Physiochemical Property Profiles of Develop-
ment and Marketed Oral Drugs. J. Med. Chem. 2003, 46, 1250–1256.
(26) Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward,
K. W.; Kopple, K. D. Molecular Properties That Influence The Oral
Bioavailability of Drug Candidates. J. Med. Chem. 2002, 45, 2615–2623.
(27) Hughes, J. D.; Blagg, J.; Price, D. A.; Bailey, S.; DeCrescenzo,
G. A.; Devraj, R. V.; Ellsworth, E.; Fobian, Y. M.; Gibbs, M. E.; Gilles,
R. W.; Greene, N.; Huang, E.; Krieger-Burke, T.; Loesel, J.; Wager, T.;
Whiteley, L.; Zhang, Y. Physiochemical Drug Properties Associated
With In Vivo Toxicological Outcomes. Bioorg. Med. Chem. Lett. 2008,
18, 4872–4875.
(28) Reported SAR suggests that the three aryl rings present in
agonist 8 are the frame critical to place the substituent in the right
position to see agonism; therefore, no attempt to modify these vectors
was initiated. See ref 17 and references cited therein.
(15) 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.
(16) Hale, J. J.; Lynch, C. L.; Neway, W.; Mills, S. G.; Hajdu, R.;
Keohane, C. A.; Rosenbach, M. J.; Milligan, J. A.; Shei, G.-J.; Parent,
S. A.; Chrebet, G.; Bergstrom, J.; Card, D.; Ferrer, M.; Hodder, P.;
Strulovici, B.; Rosen, H.; Mandala, S. A Rational Utilisation of High-
Throughput Screening Affords Selective, Orally Bioavailable 1-Benzyl-3-
carboxyazetidine Sphingosine-1-phosphate-1 Receptor Agonists. J. Med.
Chem. 2004, 47, 6662–6665.
(29) S1P1 is coupled to Gi so the GTPγS assay was used to confirm
agonist function and reflects proximal signaling events induced by
agonist engagement. Loss of S1P1 function following agonist-induced
receptor internalization is the proposed mechanism of action of these
synthetic S1P1 ligands, so we also confirmed S1P1 receptor internalisa-
tion using a β-arrestin assay (a surrogate of S1P1 internalization). For
S1P3, an absence of activity was required for our compounds. In this
case, a GTPγS assay was used.
(30) A few examples with substituted 5-membered ring heterocycles
in this position were made and were all very significantly less active than
the phenyl derivative.
(31) It has not been unambiguously proven that the acid function-
ality in this template interacts with the same residues as do the
phosphates of 3 and S1P. See the following:Gonzalez-Cabrera, P. J.;
Jo, E.; Sanna, M. G.; Brown, S.; Leaf, N.; Marsolais, D.; Schaeffer, M.-T.;
Chapman, J.; Cameron, M.; Guerrero, M.; Roberts, E.; Rosen, H. Full
(17) Yan, L.; Huo, P.; Hale, J. J.; Mills, S. G.; Hajdu, R.; Keohane,
C. A.; Rosenbach, M. J.; Milligan, J. A.; Shei, G.-J.; Chrebet, G.;
Bergstrom, J.; Card, D.; Mandala, S. M. SAR studies of 3-Arylpropionic
448
dx.doi.org/10.1021/ml2000214 |ACS Med. Chem. Lett. 2011, 2, 444–449