Novel inhibitors of leukocyte transendothelial migration

Tamar Getter; Raanan Margalit; Shirin Kahremany; Laura Levy; Eliav Blum; Netaly Khazanov; Nimrod Y. Keshet-Levy; Tigist Y. Tamir; M. Ben Major; Ron Lahav; Sofia Zilber; Hanoch Senderowitz; Paul Bradfield; Beat A. Imhof; Evgenia Alpert; Arie Gruzman

doi:10.1016/j.bioorg.2019.103250

Novel inhibitors of leukocyte transendothelial migration

Tamar Getter
, Raanan Margalit
, Shirin Kahremany
, Laura Levy
, Eliav Blum
, Netaly Khazanov
, Nimrod Y. Keshet-Levy
, Tigist Y. Tamir
, M. Ben Major
, Ron Lahav
, Sofia Zilber
, Hanoch Senderowitz
, Paul Bradfield
, Beat A. Imhof
, Evgenia Alpert
, Arie Gruzman

Department of Chemistry

“Science in Action”
“AltA-ZuZ Therapeutics“
Shaare Zedek Medical Center
University of North Carolina at Chapel Hill
“MesenFlow Technologies“
University of Geneva

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

24 Scopus citations

Abstract

Leukocyte transendothelial migration is one of the most important step in launching an inflammatory immune response and chronic inflammation can lead to devastating diseases. Leukocyte migration inhibitors are considered as promising and potentially effective therapeutic agents to treat inflammatory and auto-immune disorders. In this study, based on previous trioxotetrahydropyrimidin based integrin inhibitors that suboptimally blocked leukocyte adhesion, twelve molecules with a modified scaffold were designed, synthesized, and tested in vitro for their capacity to block the transendothelial migration of immune cells. One of the molecules, namely, methyl 4-((2-(tert-butyl)-6-((2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene) methyl) phenoxy) methyl) benzoate, (compound 12), completely blocked leukocyte transendothelial migration, without any toxic effects on immune or endothelial cells (IC₅₀ = 2.4 µM). In vivo, compound 12 exhibited significant therapeutic effects in inflammatory bowel disease (IBD)/Crohn's disease, multiple sclerosis, fatty liver disease, and rheumatoid arthritis models. A detailed acute and chronic toxicity profile of the lead compound in vivo did not reveal any toxic effects. Such a type of molecule might therefore provide a unique starting point for designing a novel class of leukocyte transmigration blocking agents with broad therapeutic applications in inflammatory and auto-immune pathologies.

Original language	English
Article number	103250
Journal	Bioorganic Chemistry
Volume	92
DOIs	https://doi.org/10.1016/j.bioorg.2019.103250
State	Published - Nov 2019

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Inc.

Funding

This study was supported by a Bar-Ilan University new faculty grant (to A.G). T.G was the recipient of a Lev Zion Fellowship, Israel. S.K. is grateful for the support of her work by the Wolf Foundation, Israel. We thank Mr. Steven Manch for the English editing. This study was supported by a Bar-Ilan University new faculty grant (to A.G). T.G was the recipient of a Lev Zion Fellowship, Israel. S.K. is grateful for the support of her work by the Wolf Foundation , Israel. We thank Mr. Steven Manch for the English editing.

Funders
Wolf Foundation , Israel
Wolf Foundation
Bar-Ilan University

Keywords

Arthritis
Fatty liver
IBD/Crohn's disease
Leukocyte transmigration
Multiple sclerosis
Trioxotetrahydropyrimidin derivatives

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10.1016/j.bioorg.2019.103250

Cite this

Getter, T., Margalit, R., Kahremany, S., Levy, L., Blum, E., Khazanov, N., Keshet-Levy, N. Y., Tamir, T. Y., Ben Major, M., Lahav, R., Zilber, S., Senderowitz, H., Bradfield, P., Imhof, B. A., Alpert, E., & Gruzman, A. (2019). Novel inhibitors of leukocyte transendothelial migration. Bioorganic Chemistry, 92, Article 103250. https://doi.org/10.1016/j.bioorg.2019.103250

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abstract = "Leukocyte transendothelial migration is one of the most important step in launching an inflammatory immune response and chronic inflammation can lead to devastating diseases. Leukocyte migration inhibitors are considered as promising and potentially effective therapeutic agents to treat inflammatory and auto-immune disorders. In this study, based on previous trioxotetrahydropyrimidin based integrin inhibitors that suboptimally blocked leukocyte adhesion, twelve molecules with a modified scaffold were designed, synthesized, and tested in vitro for their capacity to block the transendothelial migration of immune cells. One of the molecules, namely, methyl 4-((2-(tert-butyl)-6-((2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene) methyl) phenoxy) methyl) benzoate, (compound 12), completely blocked leukocyte transendothelial migration, without any toxic effects on immune or endothelial cells (IC50 = 2.4 µM). In vivo, compound 12 exhibited significant therapeutic effects in inflammatory bowel disease (IBD)/Crohn's disease, multiple sclerosis, fatty liver disease, and rheumatoid arthritis models. A detailed acute and chronic toxicity profile of the lead compound in vivo did not reveal any toxic effects. Such a type of molecule might therefore provide a unique starting point for designing a novel class of leukocyte transmigration blocking agents with broad therapeutic applications in inflammatory and auto-immune pathologies.",

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author = "Tamar Getter and Raanan Margalit and Shirin Kahremany and Laura Levy and Eliav Blum and Netaly Khazanov and Keshet-Levy, \{Nimrod Y.\} and Tamir, \{Tigist Y.\} and \{Ben Major\}, M. and Ron Lahav and Sofia Zilber and Hanoch Senderowitz and Paul Bradfield and Imhof, \{Beat A.\} and Evgenia Alpert and Arie Gruzman",

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doi = "10.1016/j.bioorg.2019.103250",

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AU - Margalit, Raanan

AU - Kahremany, Shirin

AU - Levy, Laura

AU - Blum, Eliav

AU - Khazanov, Netaly

AU - Keshet-Levy, Nimrod Y.

AU - Tamir, Tigist Y.

AU - Ben Major, M.

AU - Lahav, Ron

AU - Zilber, Sofia

AU - Senderowitz, Hanoch

AU - Bradfield, Paul

AU - Imhof, Beat A.

AU - Alpert, Evgenia

AU - Gruzman, Arie

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AB - Leukocyte transendothelial migration is one of the most important step in launching an inflammatory immune response and chronic inflammation can lead to devastating diseases. Leukocyte migration inhibitors are considered as promising and potentially effective therapeutic agents to treat inflammatory and auto-immune disorders. In this study, based on previous trioxotetrahydropyrimidin based integrin inhibitors that suboptimally blocked leukocyte adhesion, twelve molecules with a modified scaffold were designed, synthesized, and tested in vitro for their capacity to block the transendothelial migration of immune cells. One of the molecules, namely, methyl 4-((2-(tert-butyl)-6-((2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene) methyl) phenoxy) methyl) benzoate, (compound 12), completely blocked leukocyte transendothelial migration, without any toxic effects on immune or endothelial cells (IC50 = 2.4 µM). In vivo, compound 12 exhibited significant therapeutic effects in inflammatory bowel disease (IBD)/Crohn's disease, multiple sclerosis, fatty liver disease, and rheumatoid arthritis models. A detailed acute and chronic toxicity profile of the lead compound in vivo did not reveal any toxic effects. Such a type of molecule might therefore provide a unique starting point for designing a novel class of leukocyte transmigration blocking agents with broad therapeutic applications in inflammatory and auto-immune pathologies.

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ER -

Novel inhibitors of leukocyte transendothelial migration

Abstract

Bibliographical note

Funding

Keywords

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