Selectin inhibitors

Zanini D, Roy R, Park WKC, Foxall C, Srivastava OP (1996) 3 -Sulfo-LewisX-Glc den-drimers as potent l- and E-selectin inhibitors. Proceedings of the XVIIIth International Carbohydrate Symposium, Milan, Italy, July 21-26, p 543... 

A number of different competitive cell-free and cell-based binding assays under static and hydrodynamic flow conditions have been used to obtain affinity data for selectin ligands. In addition to the fact that different positive controls have been used, this makes a direct comparison of reported binding affinities difficult. Therefore, in this chapter, we quote relative affinities wherever possible (Section 16.4.3). Another problem that has a negative effect on assay reliabihty has been encountered in cases where acidic ion exchange resins are used in the final step of the antagonist synthesis [170]. Small amounts of polyanions released from the resin were found to be potent selectin inhibitors, especially for P-selectin. These polyanions are difficult to remove and are not detectable by routine analysis. As a result, published assay data for P-selectin antagonists should be considered with caution. 

Based on this lead, several academic and industrial groups have designed selectin inhibitors with improved pharmacodynamic and pharmacokinetic properties. The major goals (besides... 

Rao, B N N, Anderson, M B, Musser, J H, Gilbert, J H, Schaefer, M E, Eoxah, C, Brandley, B K, Sialyl Lewis mimics derived from a pharmacophore search are selectin inhibitors with antiinflammatory activity, J. Biol. Chem., 269, 19663-19666, 1994. 

Pabna-Vargas, J M, Toledo-Pereyra, L, Dean, R E, Harkema, JM, Dixon, R A E, Kogan, T P, Small-molecule selectin inhibitor protects against bver inflammatory response after ischemia and reperfusion, J. Am. Coll. Surg., 185, 365-372, 1997. 

Dasgupta, F, Musser, J H, Levy, D E, and Tang, P C, Preparation of Eucose-Containing Siahc Acids as Selectin Inhibitors, U.S. Patent 5658880, 1997. 

Many of the individual topics addressed in the present chapter have been discussed in the context of excellent specialist reviews. Some of these are cited in the respective sections. Wong and his associates have prepared a comprehensive review entitled Selectin-Carbohydrate Interactions from Natural Ligands to Designed Mimics which provides a complete survey of the literature dealing especially with the medicinal chemistiy aspects of selectin inhibitor design treatment of this aspect has therefore been restricted to a few representative examples in the present article. Vcstwcbcr has edited a comprehensive monograph entitled The Selectins Initiators of Leukocyte Endothelial Adhesion. 

Many biological processes take place under dynamic rather than static conditions. For example, the ability of the selectins to mediate the dynamic process of leukocyte rolling is a critical aspect of their function yet most selectin inhibitors have been evaluated in static assays. A smdy evaluating multivalent L-selectin inhibitors revealed dramatic differences in their activities in static cell free versus dynamic cell rolling assays. 

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