Rational Design of Novel, Potent Small Molecule Pan-Selectin Antagonists

Abstract

This report describes the first results of a rational hit-finding strategy to design novel small molecule antiinflammatory drugs targeting selectins, a family of three cellular adhesion molecules. Based on recent progress in understanding of molecular interaction between selectins and their natural ligands as well as progress in clinical development of synthetic antagonists like 1 (bimosiamose, TBC1269), this study was initiated to discover small molecule selectin antagonists with improved pharmacological properties. Considering 1 as template structure, a ligand-based approach followed by focused chemical synthesis has been applied to yield novel synthetic small molecules (MWr < 500) with a trihydroxybenzene motif, bearing neither peptidic nor glycosidic components, with nanomolar in vitro activity. Biological evaluation involves two kinds of in vitro assays, a static molecular binding assay, and a dynamic HL-60 cell attachment assay. As compared to controls, the novel compounds showed improved biological in vitro activity both under static and dynamic conditions.

Targeting P-selectin glycoprotein ligand-1/P-selectin interactions as a novel therapy for metabolic syndrome

“…Fundamentally, high affinity PSGL-1/P-selectin binding requires stereospecific interactions with clustered tyrosine sulfates (Tyr-SO3H), as well as a core-2 O-glycan, which has a sLe x containing hexasaccharide (C2-O-sLe x ) [135–137]. To date, the design of most existing P-selectin inhibitors has focused on mimicking the C2 O-glycan bearing sLe x moiety and in so doing, these approaches have been largely unsuccessful in accounting for the contribution of critical clustered tyrosine sulfates [119, 124, 130, 131, 138, 139]. Further synthetic challenges have included suboptimal selectivity in glycosylation [140], incompatible protecting groups for the synthesis of oligosaccharides [141], and the acid lability of tyrosine sulfates [142, 143], all of which have contributed to low yield of PSGL-1 GSP mimetics.…”

Navigating the Human Metabolome for Biomarker Identification and Design of Pharmaceutical Molecules

“…It is has been isolated from black currant [52], which has long been used in European and Chinese folk medicine as diuretic, treating diarrhea, arthritic pain, and so forth. Recently, 2-pyrocatechuic acid was found to be weak inhibitor of Selectin E [53] and potent inhibitor of 15-lipogygenase-catalysed oxygenation of arachidonic acid that is involved in many aspects of inflammatory disease and in particular in the development of colorectal cancer [54]. …”

E- and P-Selectin: Differences, Similarities and Implications for the Design of P-Selectin Antagonists

“…5. [23] For the best representatives, low micromolar affinities in a static cell free assay and significant inhibition of HL-60 cell attachment to selectins under flow conditions are reported. Although initially designed to mimic sLe x , the authors also consider the possibility of alternative binding modes.…”