Quinic Acid Derivatives as Sialyl Lewis^x-Mimicking Selectin Inhibitors:  Design, Synthesis, and Crystal Structure in Complex with E-Selectin

Abstract

A search for noncarbohydrate sLe(x) mimics led to the development of quinic acid derivatives as selectin inhibitors. At Wyeth we solved the first cocrystal structure of a small molecule, quinic acid, with E-selectin. In the cocomplex two hydroxyls of quinic acid mimic the calcium-bound fucose of the tetrasaccharide sLe(x). The X-ray structure, together with structure based computational methods, was used to design quinic acid based libraries that were synthesized and evaluated for their ability to block the interaction of sLex with P-selectin. A large number of analogues were prepared using solution-phase parallel synthesis. Selected compounds showed decrease in leukocyte rolling in the IVM mouse model. Compound 2 inhibited neutrophil influx in the murine TIP model and demonstrated good plasma exposure.

Discovery of Quinic Acid Derivatives as Oral Anti-inflammatory Agents

“…67,68 These same authors showed that the presence of a carboxylic acid functional group was necessary for interaction with the selectins. 67,68 A seriels of QA amides will be prepared, then go to biological screening against our NF-κB activity HTS System. QA amide leads will form a new template for anti-inflammatory agents.…”

“…See Figure 1-3 from Vink et al 66 Recent work has demonstrated an interaction of QA derivatives with the carbohydrate binding proteins (lectins) involved in key leukocyte-endothelial cell interactions. 67,68 Tetrasaccharide sialyl Lewis x (sLex) ligands found on leukocytes contain sialic acid, L-fucose, and galactose which are essential for calcium-mediated binding of sLex to the carbohydrate binding proteins E, P, and L-selectin. Tetrasaccharide sLex exhibits a poor pharmacokinetic profile and thus cannot be developed as a selectin inhibitor.…”

“…A search for druggable sLex mimetics led to the substitution of QA for fucose since the hydroxyl groups of QA mimic hydroxyl groups of fucose which make key interactions with protein side chains that bind calcium. 67,68 Selective QA analogs were shown to decrease leukocyte rolling in response to LPS in an intravital microscopy mouse model and to decrease neutrophil influx in a murine thioglycollate-induced peritonitis model. 68 Others have shown that selective QA analogs interact weakly with both P-and E-selectin using HL-60 cells.…”

“…67,68 Selective QA analogs were shown to decrease leukocyte rolling in response to LPS in an intravital microscopy mouse model and to decrease neutrophil influx in a murine thioglycollate-induced peritonitis model. 68 Others have shown that selective QA analogs interact weakly with both P-and E-selectin using HL-60 cells. QA has been confirmed as antioxidant, and extends its mode of action to include a basic nutritional benefit due to the enhanced metabolism of both tryptophan and nicotinamide.…”

“…A review prepared by Barco has comprehensively covered QA chemistry literature up to the beginning of 1997. synthesized QA derivatives as sialyl lewis x -mimicking selectin inhibitors in order to target E-selectin. 67,68 Kim made analogues as influenza neuraminidase inhibitors with potent anti-anfluenza activity. 91 Sanchez-Sixto and Metaferia made compounds to kill Mycobacterium tuberculosis.…”