Discovery of Novel Sphingosine-1-Phosphate-1 Receptor Agonists for the Treatment of Multiple Sclerosis

Sun Jun Park; Seul Ki Yeon; Yoowon Kim; Hyeon Jeong Kim; Siwon Kim; Jushin Kim; Ji Won Choi; Byungeun Kim; Elijah Hwejin Lee; Rium Kim; Seon Hee Seo; Jaeick Lee; Jun Woo Kim; Ha Yeon Lee; Hayoung Hwang; Yong Sun Bahn; Eunji Cheong; Jong Hyun Park; Ki Duk Park

doi:10.1021/acs.jmedchem.1c01979

Discovery of Novel Sphingosine-1-Phosphate-1 Receptor Agonists for the Treatment of Multiple Sclerosis

Sun Jun Park, Seul Ki Yeon, Yoowon Kim, Hyeon Jeong Kim, Siwon Kim, Jushin Kim, Ji Won Choi, Byungeun Kim, Elijah Hwejin Lee, Rium Kim, Seon Hee Seo, Jaeick Lee, Jun Woo Kim, Ha Yeon Lee, Hayoung Hwang, Yong Sun Bahn, Eunji Cheong, Jong Hyun Park, Ki Duk Park

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

The sphingosine-1-phosphate-1 (S1P₁) receptor agonists have great potential for the treatment of multiple sclerosis (MS) because they can inhibit lymphocyte egress through receptor internalization. We designed and synthesized triazole and isoxazoline derivatives to discover a novel S1P₁agonist for MS treatment. Of the two scaffolds, the isoxazoline derivative was determined to have excellent in vitro efficacy and drug-like properties. Among them, compound 21l was found to have superior drug-like properties as well as excellent in vitro efficacies (EC₅₀= 7.03 nM in β-arrestin recruitment and EC₅₀= 11.8 nM in internalization). We also confirmed that 21l effectively inhibited lymphocyte egress in the peripheral lymphocyte count test and significantly improved the clinical score in the experimental autoimmune encephalitis MS mouse model.

Original language	English
Pages (from-to)	3539-3562
Number of pages	24
Journal	Journal of Medicinal Chemistry
Volume	65
Issue number	4
DOIs	https://doi.org/10.1021/acs.jmedchem.1c01979
Publication status	Published - 2022 Feb 24

Bibliographical note

Funding Information:
This study was supported by the National Research Foundation of Korea (NRF-2018M3A9C8016849) and the Korea Institute of Science and Technology (KIST) Institutional Program (2E31522).

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.1c01979

Cite this

Park, S. J., Yeon, S. K., Kim, Y., Kim, H. J., Kim, S., Kim, J., Choi, J. W., Kim, B., Lee, E. H., Kim, R., Seo, S. H., Lee, J., Kim, J. W., Lee, H. Y., Hwang, H., Bahn, Y. S., Cheong, E., Park, J. H., & Park, K. D. (2022). Discovery of Novel Sphingosine-1-Phosphate-1 Receptor Agonists for the Treatment of Multiple Sclerosis. Journal of Medicinal Chemistry, 65(4), 3539-3562. https://doi.org/10.1021/acs.jmedchem.1c01979

Park, Sun Jun ; Yeon, Seul Ki ; Kim, Yoowon ; Kim, Hyeon Jeong ; Kim, Siwon ; Kim, Jushin ; Choi, Ji Won ; Kim, Byungeun ; Lee, Elijah Hwejin ; Kim, Rium ; Seo, Seon Hee ; Lee, Jaeick ; Kim, Jun Woo ; Lee, Ha Yeon ; Hwang, Hayoung ; Bahn, Yong Sun ; Cheong, Eunji ; Park, Jong Hyun ; Park, Ki Duk. / Discovery of Novel Sphingosine-1-Phosphate-1 Receptor Agonists for the Treatment of Multiple Sclerosis. In: Journal of Medicinal Chemistry. 2022 ; Vol. 65, No. 4. pp. 3539-3562.

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title = "Discovery of Novel Sphingosine-1-Phosphate-1 Receptor Agonists for the Treatment of Multiple Sclerosis",

abstract = "The sphingosine-1-phosphate-1 (S1P1) receptor agonists have great potential for the treatment of multiple sclerosis (MS) because they can inhibit lymphocyte egress through receptor internalization. We designed and synthesized triazole and isoxazoline derivatives to discover a novel S1P1agonist for MS treatment. Of the two scaffolds, the isoxazoline derivative was determined to have excellent in vitro efficacy and drug-like properties. Among them, compound 21l was found to have superior drug-like properties as well as excellent in vitro efficacies (EC50= 7.03 nM in β-arrestin recruitment and EC50= 11.8 nM in internalization). We also confirmed that 21l effectively inhibited lymphocyte egress in the peripheral lymphocyte count test and significantly improved the clinical score in the experimental autoimmune encephalitis MS mouse model.",

author = "Park, {Sun Jun} and Yeon, {Seul Ki} and Yoowon Kim and Kim, {Hyeon Jeong} and Siwon Kim and Jushin Kim and Choi, {Ji Won} and Byungeun Kim and Lee, {Elijah Hwejin} and Rium Kim and Seo, {Seon Hee} and Jaeick Lee and Kim, {Jun Woo} and Lee, {Ha Yeon} and Hayoung Hwang and Bahn, {Yong Sun} and Eunji Cheong and Park, {Jong Hyun} and Park, {Ki Duk}",

note = "Funding Information: This study was supported by the National Research Foundation of Korea (NRF-2018M3A9C8016849) and the Korea Institute of Science and Technology (KIST) Institutional Program (2E31522). Publisher Copyright: {\textcopyright} 2022 American Chemical Society. All rights reserved.",

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doi = "10.1021/acs.jmedchem.1c01979",

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Park, SJ, Yeon, SK, Kim, Y, Kim, HJ, Kim, S, Kim, J, Choi, JW, Kim, B, Lee, EH, Kim, R, Seo, SH, Lee, J, Kim, JW, Lee, HY, Hwang, H, Bahn, YS , Cheong, E, Park, JH & Park, KD 2022, 'Discovery of Novel Sphingosine-1-Phosphate-1 Receptor Agonists for the Treatment of Multiple Sclerosis', Journal of Medicinal Chemistry, vol. 65, no. 4, pp. 3539-3562. https://doi.org/10.1021/acs.jmedchem.1c01979

Discovery of Novel Sphingosine-1-Phosphate-1 Receptor Agonists for the Treatment of Multiple Sclerosis. / Park, Sun Jun; Yeon, Seul Ki; Kim, Yoowon; Kim, Hyeon Jeong; Kim, Siwon; Kim, Jushin; Choi, Ji Won; Kim, Byungeun; Lee, Elijah Hwejin; Kim, Rium; Seo, Seon Hee; Lee, Jaeick; Kim, Jun Woo; Lee, Ha Yeon; Hwang, Hayoung; Bahn, Yong Sun ; Cheong, Eunji; Park, Jong Hyun; Park, Ki Duk.

In: Journal of Medicinal Chemistry, Vol. 65, No. 4, 24.02.2022, p. 3539-3562.

Research output: Contribution to journal › Article › peer-review

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T1 - Discovery of Novel Sphingosine-1-Phosphate-1 Receptor Agonists for the Treatment of Multiple Sclerosis

AU - Park, Sun Jun

AU - Yeon, Seul Ki

AU - Kim, Yoowon

AU - Kim, Hyeon Jeong

AU - Kim, Siwon

AU - Kim, Jushin

AU - Choi, Ji Won

AU - Kim, Byungeun

AU - Lee, Elijah Hwejin

AU - Kim, Rium

AU - Seo, Seon Hee

AU - Lee, Jaeick

AU - Kim, Jun Woo

AU - Lee, Ha Yeon

AU - Hwang, Hayoung

AU - Bahn, Yong Sun

AU - Cheong, Eunji

AU - Park, Jong Hyun

AU - Park, Ki Duk

N1 - Funding Information: This study was supported by the National Research Foundation of Korea (NRF-2018M3A9C8016849) and the Korea Institute of Science and Technology (KIST) Institutional Program (2E31522). Publisher Copyright: © 2022 American Chemical Society. All rights reserved.

PY - 2022/2/24

Y1 - 2022/2/24

N2 - The sphingosine-1-phosphate-1 (S1P1) receptor agonists have great potential for the treatment of multiple sclerosis (MS) because they can inhibit lymphocyte egress through receptor internalization. We designed and synthesized triazole and isoxazoline derivatives to discover a novel S1P1agonist for MS treatment. Of the two scaffolds, the isoxazoline derivative was determined to have excellent in vitro efficacy and drug-like properties. Among them, compound 21l was found to have superior drug-like properties as well as excellent in vitro efficacies (EC50= 7.03 nM in β-arrestin recruitment and EC50= 11.8 nM in internalization). We also confirmed that 21l effectively inhibited lymphocyte egress in the peripheral lymphocyte count test and significantly improved the clinical score in the experimental autoimmune encephalitis MS mouse model.

AB - The sphingosine-1-phosphate-1 (S1P1) receptor agonists have great potential for the treatment of multiple sclerosis (MS) because they can inhibit lymphocyte egress through receptor internalization. We designed and synthesized triazole and isoxazoline derivatives to discover a novel S1P1agonist for MS treatment. Of the two scaffolds, the isoxazoline derivative was determined to have excellent in vitro efficacy and drug-like properties. Among them, compound 21l was found to have superior drug-like properties as well as excellent in vitro efficacies (EC50= 7.03 nM in β-arrestin recruitment and EC50= 11.8 nM in internalization). We also confirmed that 21l effectively inhibited lymphocyte egress in the peripheral lymphocyte count test and significantly improved the clinical score in the experimental autoimmune encephalitis MS mouse model.

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Discovery of Novel Sphingosine-1-Phosphate-1 Receptor Agonists for the Treatment of Multiple Sclerosis

Abstract

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