A novel class of potent nonglycosidic and nonpeptidic pan-selectin inhibitors.
Journal of medicinal chemistry 2006 Oct 5; 49(20):5988-99
Ulbrich H HK, Luxenburger A A, Prech P P, Eriksson E EE, Soehnlein O O, Rotzius P P, Lindbom L L, Dannhardt G G
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Johannes Gutenberg University, Staudingerweg 5, DE-55099 Mainz, Germany. ulbrich@uni-mainz.de
An early step of the inflammatory response, the rolling of leukocytes on activated endothelial cells, is mediated by selectin/carbohydrate interactions. The tetrasaccharide sialy Lewisx is a ligand for E-, P-, and L-selectin and therefore serves as a lead structure for the development of analogues. A combination of synthesis and structure-based design allowed rapid optimization. The current lead 2a was evaluated in our E-selectin cell flow chamber assay where it proved to inhibit rolling and adhesion with an IC50 of 28+/-7 microM. The assays used are predictive for the in vivo efficacy of test compounds as shown for 2a in a proteose peptone induced peritonitis model of acute inflammation in mice.