P-selectin inhibitors

Discovery of PSI 421, a P-Selectin inhibitor with improved pharmacokinetic properties and oral efficacy in models of vascular injury... 

Maiming DD, Hu X, Beck P, Kiessling LL (1997) Synthesis of sulfated neoglycopolymers selective P-selectin inhibitors. J Am Chem Soc 119(13) 3161-3162... 

SNAC is the most potent inhibitor of collagen-induced platelet aggregation in vitro compared to other S-nitrosothiols (SNAP, GSNO, CysNO and HomocysNo). Although it increased cGMP-levels in platelets [47], SNAC only partially inhibited thrombin-induced P-selectin expression on a platelet surface [79]. 

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... 

Cilostazol is a PDE3 inhibitor and also is a drug with multiple mechanisms of action (23,24), some of which are directly platelet-related, and others of which exert their effects indirectly via endothelial cells (Figs, 4 and 5), As a PDE inhibitor, it increases the concentration of cyclic nucleotides within platelets and inhibits platelet aggregation in response to shear forces (via ADP) and a variety of agonists. Like other inhibitors of platelet activation, it blocks the expression and release of P-selectin, a key adhesion molecule on the membrane of platelet alpha granules that externalizes with activation, and plays an important role in the interactions between platelets, endothelial cells, and leukocytes, The effect of cilostazol on P-selectin expression appears to be additive to those of aspirin and clopidogrel (25). 

As previously mentioned, for SMC proliferation after coronary angioplasty, cell activation and cell-to-cell interaction of platelets and leukocytes mediated by adhesion molecules are considered to be important. Coronary stenting produces the release of an adhesion molecule, P-selectin, from d-granule of activated platelets. P-selectin-mediated platelet-leukocyte interaction has a crucial role in the development of stent restenosis. Cilostazol is an antiplatelet, antithrombotic, phosphodiesterase III inhibitor that by inhibiting P-selectin release has inhibitory effects on SMC migration. In addition, cilostazol may directly act to inhibit intimal hyperplasia. 

Jenison RD, Jennings SD, Walker DW, Bargatze RF, Oligonucleotide inhibitors of P-selectin-dependent neutrophil-platelet adhesion, Antisense Nucleic Acid Drug Dev, 8 265-279, 1998. 

There are several lines of evidence demonshahng that CSA causes endothelial cell injury. CSA has a direct cytotoxic effect on cultured endothelial cells and inhibits human umbilical endothelial cell proliferahon [74,75]. CSA increases the plasma level of endothelial damage markers, such as Von Willebrand factor, endothelin tissue factor pathway inhibitor, P-selectin and thrombin-antithrombin complexes in renal and heart transplant patients [76-79]. Similarly, the release of Von... 

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. 

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. 

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