ICAM-1 inhibitors

Cellular responses, as measured by a mixed-lymphocyte reaction, cytotoxic T lymphocyte response, and NK cell activity, were all undiminished, and if anything, there was a slight increase in CTL and NK responses. As would be expected by the histologic profile and the known increases in cytokine and chemokine production associated with the administration of PS ODNs in rodents, in this series of experiments there was no diminution in immune response. Administering a mouse-specific ICAM-1 inhibitor produced reductions in mixed lymphocyte reactions. This inhibition was expected as this is one of the desired pharmacologic effects of reducing ICAM-1 expression. 

The quaternization method is also highlighted by the short asymmetric synthesis of cell adhesion molecule BIRT-377 (Scheme 5.24), which is a potent inhibitor of the interaction between intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) [16]. Thus, asymmetricp-bromobenzylation of the alanine derivative 42 (R1 = Me) with (S)-18 under similar phase-transfer conditions as described above gave rise to p-bromobenzylalanine ester 10 in 97% ee (83% yield). A similar asymmetric p-bromobenzylation of alanine ethyl ester 42 (R1 = Me, R= Et) gave the amino ester 47 (R= Et) in 90% ee (86% yield). The amino ester 47 (R = t-Bu or Et) was treated with 3,5-dichlorophenyl isocyanate in the presence of sodium carbonate in dimethylsulfoxide (DMSO) to furnish the hydantoin 48 in 86%... 

The n-3 PUFAs are reported to reduce expression of endothelial adhesion molecules VCAM-1, E-selectin, and ICAM-1, therefore influencing leukocyte-endothelial cell interactions and leukocyte migration across the endothelium. 105,106 Oxidized EPA has been shown to be a more potent inhibitor of leukocyte-endothelial interaction, in vitro and in vivo, than EPA.107 Since EFAs regulate intercellular adhesion, it has been speculated that the skin changes that are observed in EFA deficiency, may be due, at least in part, to damaged cell adhesion.108 n-3 PUFAs and GLA supplementation enhance E-cadherin expression in cancer cells and this possibly reduces the invasiveness of these cells.109... 

Alicaforsen - Isis Pharmaceuticals Antisense oligonucleotide Phase 3 Inhibitor of intracellular adhesion molecule-1 (ICAM-1) Crohn s disease... 

Henry SP, Denny KH, Templin MV, Yu RZ, Levin AA. Effects of human and murine antisense ohgonucleotide inhibitors of ICAM-1 on reproductive performance, fetal development, and post-natal development in mice. Birth Defects Res 2004 71 359-67. 

Selective adhesion molecule inhibitor produced in murine myeloma cells, binds to o 4-submunit of human integrin which is highly expressed on the surface of all leukocytes, with exception of neutrophils and blocks the interaction with vascular cell adhesion molecule-1 (ICAM-1)... 

Complement Activation. With 2-h infusions at a dose of 2 mg/kg, no increases in complement-split products were observed in more than 300 patients with inflammatory diseases treated with ISIS 2302, a 20-nucleotide phosphorothioate antisense inhibitor of ICAM-1. Similarly, ISIS 5132, an inhibitor of C-raf kinase was dosed from 0.5 to 6.0 mg/kg and no meaningful increases in complement-split products were observed. ISIS 3521, a PKCa inhibitor gave equivalent data and both of these drugs were studied in patients with various malignant diseases. Similar data were observed with all the phosphorothioate oligodeoxynucleotides administered on this... 

Table 14. Effects of PKC inhibitor H7 and baicalein on ELAM-1 and ICAM-1 expression induced by PMA, thrombin and TRAP in cultured HUVECs1...

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