Cell adhesion molecule inhibitors

A 3D model of the fibrinogen-derived (very late antigen-4, VLA-4) inhibitor 4-[N -(2-methylphenyl)ureido]phenylacetyl-Leu-Asp-Val was derived from the X-ray structure of the related integrin-binding region of the vascular cell adhesion molecule-1 (VCAM-1). A 3D pharmacophore was generated with the program Catalyst, and a 3D search was performed in 8624 molecules from... 

Halichlorine 11 is a structurally unique alkaloid that was isolated from the sponge Halichondria okadai and found to act as an inhibitor of the induction of vascular cell adhesion molecule (VCAM-1), a potential target in the development of drugs for the treatment of several vascular diseases. The strategies employed for the construction of its spiroquinolizidine unit are summarized in Scheme 106. 

As stated earlier, activation of endothelial cells by pro-inflammatory stimuli leads to the expression of cell adhesion molecules and cytokines such as IL-6 and IL-8. The expression and hence modulation of surface expressed adhesion molecules by e.g. targeted delivery of inhibitors of NFkB, can be measured using flow cytometric analysis or whole cell ELISA techniques. Cytokine production can be measured in the supernatant of cultured cells or in biological fluids. Furthermore, competitive or quantitative RT-PCR analysis of mRNA levels of cell adhesion molecules or cytokines, allows the transcriptional activity of the genes of interest to be estimated. 

Cyclic peptide inhibitors of VLA-1 and fibronectin/vascular cell adhesion molecule... 

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%... 

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)... 

In demyelination such as MS, PSA-NCAM is expressed on denuded axons and might act as an inhibitor of remyelination, whereas the myelinated part outside the plaque is PSA-NCAM negative (Charles et al., 2000 Coman et al., 2005). On the other hand, in MS a two- to threefold increase in OPC density and proliferation was found in the subventricular zone (SVZ), which correlated with enhanced numbers of PSA-NCAM(-i-) cells (Nait-Oumesmar et al., 2007). EAE in rodents is another important example of the activation of the SVZ and the involvement of progenitor cells expressing the polysialylated form of neural cell adhesion molecule (PSA-NCAM) in the repair process (Picard-Riera et al., 2002). 

It was observed that rats with a transient MCA occlusion have a larger brain infarction when recombinant human IL-1 P is injected into the lateral ventricle immediately after reperfusion [7,41]. Similar results have been obtained in rats with a permanent MCA occlusion [7,42]. The intraventricular injection of recombinant human IL-1 p also enhances the formation of brain edema and increases both the number of neutrophils in ischemic areas and neutrophil-endothelial cell adhesion. The most widely recognized functions of IL-1 appear to be the induction of endothelial cell adhesion molecule expression and the promotion of neutrophil tissue infiltration [7,41]. These observations suggest that IL-1 may play a deleterious role in cerebral ischemia. Studies showing a reduction in infarct size after the administration of IL-1 antagonists or inhibitors provide further evidence of the importance of IL-1 in cerebral ischemia [41,43-49]. The possible harmful mechanisms induced or activated by IL-1 include fever, increased heart rate and arterial blood pressure, enhancement of N-methyl-D-aspartate-mediated injury, proliferation of microglia, release of arachidonic acid, and stimulation of NO synthesis [7,50]. 

Hayashi, M., Kim, Y.-R, Hiraoka, H., Natori, M., Takamatsu, S., Kawakubo, T, Masuma, R., Komiyama, K., and Omura, S. (1995). Macrosphelide, a novel inhibitor of cell-cell adhesion molecule. I. Taxonomy, fermentation, isolation and biological activities. J. Antibiot. 48, 1435-1439. 

In the search for inhibitors of cell adhesion molecule expression in human endothelial cells, thieno[23-d]pyrimidin-4-one 36 was first subjected to a Krapcho dccarboethoxylation. The resultant pyrimidone was then converted to 4-chlorothieno[23-leaving group, new C-S and C-N bond formations were easily achieved by SnAf displacements to produce 38 <01JMC988>. Yields were not given for all compounds... 

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