Maher Qabar

Highly efficient and versatile synthesis of libraries of constrained β-strand mimetics

The general approach of using a bicyclic template to produce inhibitors of the protease superfamily of enzymes has been investigated. The Diels-Alder cycloaddition reaction on solid support has been found to be highly efficient for the synthesis of libraries of compounds that mimic the β-strand secondary structure of proteins. Several potent and selective inhibitors of proteases have been discovered.

[1+4] Cycloaddition of vinyl isocyanates with isocyanides. Construction of functionally elaborate pyrrolinone derivatives

Abstract Reaction of alkyl isocyanides with vinyl isocyanates affords highly functionalized pyrrolinone and hydroindolone products via a novel [1+4] cyclization process.

High-throughput synthesis and optimization of thrombin inhibitors via urazole α-addition and Michael addition

A novel alpha-addition of propiolates to urazoles followed by Michael addition of a variety of nucleophiles has been developed for rapid production and optimization of peptidomimetic drug leads. This technology has produced a number of highly potent and selective inhibitors of the serine protease, thrombin.

A facile solution and solid phase synthesis of phosphotyrosine mimetic l-4-[diethylphosphono(difluoromethyl)]-phenylalanine (F2Pmp(EtO)2) derivatives

The F2Pmp derivatives were prepared in 80–90% yield from commercially available protected l-4-iodophenylalanine by esterification with diazomethane followed by a CuCl-mediated coupling to (diethylphosphonyl) difluoromethylcadmium bromide. Moreover, treatment of l-4-iodoPhe-containing peptides under the same coupling conditions provided the F2Pmp-containing peptides in very good yields.

Design and Synthesis of Phosphotyrosine Mimetics

Selective inhibitors of protein tyrosine phosphatases (PTPases) are of great interest as therapeutic agents and research tools. Several phenylalanine derivatives (1, 2) designed as phosphotyrosine mimetics or irreversible active site inhibitors were successfully synthesized, then incorporated into a combinatorial library based on a peptidomimetic beta-strand template.

EFFICIENT SYNTHESIS OF NOVEL 4-SUBSTITUTED URAZOLES

ABSTRACT The efficient synthesis of several new and novel 4-substituted triazolidindiones (urazoles) starting from isocyanates, amines, anilines and carboxylic acids is reported.

Pharmaceutical applications of peptidomimetics

Nature has used a ‘library approach’ to constructing ligands for specific receptors and enzymes by combining a limited functional diversity of 20 amino acid side chains with a small array of secondary structure motifs — reverse turns, α-helices and β-strands. The dissection of multidomain proteins into small synthetic conformationally restricted components is an important step in the design of low-molecular-weight nonpeptides that mimic the activity of the native protein. Mimetics of critical functional domains might possess beneficial properties with regard to specificity and therapeutic potential compared to the intact proteinaceous species. Combinatorial secondary-structure-templated libraries provide a powerful engine for the development of novel vaccines and pharmaceuticals.

An Experimentally Convenient Preparation of Highly Substituted Pyridines

Abstract A four step sequence is described for the conversion of α,β-unsaturated carboxylic acids into highly substituted pyridines.

Asymmetric synthesis and conformational analysis of the two enantiomers of the saturated analog of the potent thrombin inhibitor MOL-376

Abstract Asymmetric synthesis of the two enantiomers of a small molecule thrombin inhibitor is described. The key step in the synthesis is the glucose-directed chiral induction in the hetero Diels–Alder cycloaddition step. Conformational analysis indicates that the S -enantiomer is a better fit for the idealized β-strand conformation.

Sulphonamide-based small molecule VLA-4 antagonists

The discovery of a sulphonamide by-product with VLA-4 antagonistic activity led to a series of potent, small molecule VLA-4 antagonists. Synthesis, SAR and in vivo evaluation of the selected compound will be presented.