TY - JOUR
T1 - Novel inhibitors of leukocyte transendothelial migration
AU - Getter, Tamar
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
N1 - Publisher Copyright: © 2019 Elsevier Inc.
PY - 2019/11
Y1 - 2019/11
N2 - 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.
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.
KW - Arthritis
KW - Fatty liver
KW - IBD/Crohn's disease
KW - Leukocyte transmigration
KW - Multiple sclerosis
KW - Trioxotetrahydropyrimidin derivatives
UR - http://www.scopus.com/inward/record.url?scp=85072693966&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.bioorg.2019.103250
DO - https://doi.org/10.1016/j.bioorg.2019.103250
M3 - مقالة
C2 - 31580982
SN - 0045-2068
VL - 92
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
M1 - 103250
ER -