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

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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 languageEnglish
Article number103250
JournalBioorganic Chemistry
StatePublished - Nov 2019

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Inc.


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


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