Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Nov 15:96:129516.
doi: 10.1016/j.bmcl.2023.129516. Epub 2023 Oct 11.

Imidazole-based sphingosine-1-phosphate transporter Spns2 inhibitors

Christopher W Shrader  1 , Daniel Foster  1 , Yugesh Kharel  2 , Tao Huang  2 , Kevin R Lynch  2 , Webster L Santos  3
Affiliations

Imidazole-based sphingosine-1-phosphate transporter Spns2 inhibitors

Christopher W Shrader et al. Bioorg Med Chem Lett. .

Abstract

Sphingosine-1-phosphate (S1P) is a chemotactic lipid that influences immune cell positioning. S1P concentration gradients are necessary for proper egress of lymphocytes from the thymus and secondary lymphoid tissues. This trafficking is interdicted by S1P receptor modulators, and it is expected that S1P transporter (Spns2) inhibitors, by reshaping S1P concentration gradients, will do the same. We previously reported SLF1081851 as a prototype Spns2 inhibitor, which provided a scaffold to investigate the importance of the oxadiazole core and the terminal amine. In this report, we disclose a structure-activity relationship study by incorporating imidazole as both a linker and surrogate for a positive charge in SLF1081851. In vitro inhibition of Spns2-dependent S1P transport in HeLa cells identified 7b as an inhibitor with an IC50 of 1.4 ± 0.3 µM. The SAR studies reported herein indicate that imidazolium can be a substitute for the terminal amine in SLF1081851 and that Spns2 inhibition is highly dependent on the lipid alkyl tail length.

Keywords: Sphingolipids; Sphingosine-1-phosphate; Spns2; Structure–activity relationships; Transporter inhibitor.

PubMed Disclaimer

Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: W.L.S. and K.R.L. are the co-founders of S1P Therapeutics Inc, which was created to commercialize S1P-related discoveries, including Spns2 inhibitors, discovered and characterized in their laboratories.

Figures

Figure 1.
Figure 1.
S1P receptor modulating drugs: Fingolimod (Gilenya®) undergoes phosphorylation in vivo by SphK2 to the active FTY720-P; Siponimod– (Mayzent®); Ponesimod (Ponvory®); Ozanimod (Zeposia®); Etrasimod.
Figure 2.
Figure 2.
The reported Spns2 inhibitors SLF1081851 and SLB1122168.
Figure 3.
Figure 3.
Dose response curve for 7a and 7b in HeLa cells. IC50 determined to be 2.82 ± 0.6 µM and 1.4 ± 0.3 µM, respectively.
Scheme 1.
Scheme 1.
(a) (i)1-decene (1.2 equiv), 9-BBN (1.2 equiv), THF, 66 °C, 1 h; (ii) 4-bromoacetophenone (1.0 equiv), Pd(dppf)Cl2•CH2Cl2 (0.05 equiv), KOH (aq) (3.0 equiv), THF, 66 °C, 4 h, 79%; (b) NBS (1.0 equiv), p-TsOH (1.6 equiv), MeCN, 82 °C, 2 h, 82%; (c) N-Boc-GABA (1.1 equiv), K2CO3 (3.0 equiv), MeCN, rt, 16 h, 91%; (d) ammonium acetate (20 equiv), toluene, 110 °C, 5 h, 85%; (e) NaH (1.1 equiv), THF, 0 °C, 0.5 h followed by alkylhalide (1.1 equiv), THF, rt, 4 h, 29–76%; (f) 7 N NH3, MeOH, 60 °C, 24 h, 68%. (g) 4 M HCl/dioxane, CH2Cl2, rt, 2 h, 35–76%.
Scheme 2.
Scheme 2.
(a) 1H-imidazole, NaH, DMF, 0 °C, 10 min followed by 4-fluorobenzonitrile, DMF, 100 °C, 5 h, 66%; (b) NH2OH·HCl, EtOH, TEA, 80 °C, 16 h, 91%; (c) alkyl carboxylic acid, DIEA, HCTU, DMF, 100 °C, 16 h, 36–58%; (d) MeI, MeCN, 70 °C, 3 h, 30–52%.
See this image and copyright information in PMC

References

    1. Cartier A; Hla T, Sphingosine 1-phosphate: Lipid signaling in pathology and therapy. Science 2019, 366 (6463). - PMC - PubMed
    1. Goetzl EJ; Wang W; McGiffert C; Huang MC; Graler MH, Sphingosine 1-phosphate and its G protein-coupled receptors constitute a multifunctional immunoregulatory system. J. Cell. Biochem 2004, 92 (6), 1104–1114. - PMC - PubMed
    1. Hannun YA; Obeid LM, Principles of bioactive lipid signalling: lessons from sphingolipids. Nat. Rev. Mol. Cell Biol 2008, 9 (2), 139–150. - PubMed
    1. Chi H, Sphingosine-1-phosphate and immune regulation: trafficking and beyond. Trends Pharmacol. Sci 2011, 32 (1), 16–24. - PMC - PubMed
    1. Dyckman AJ, Modulators of Sphingosine-1-phosphate Pathway Biology: Recent Advances of Sphingosine-1-phosphate Receptor 1 (S1P(1)) Agonists and Future Perspectives. J. Med. Chem 2017, 60 (13), 5267–5289. - PubMed

Publication types

LinkOut - more resources