Aromatic β-Amino Acids as Asp-Phg Mimics in LDV Derived VLA-4 Antagonists­

Abstract

Aromatic b-amino acid esters 2a-h were prepared in racemic and enantiomerically pure form by the Radionow reaction or based on the method described by Davis and used as mimics of the Asp-Phg C-terminus in LDV derived VLA-4 antagonists. As a promising b-amino acid ester, 11 was identified and used for the synthesis of the highly potent VLA-4 antagonist S9059 with an IC 50 of 1.6 nM in a cell attachment assay.

Mechanochemical Preparation of 3,5-Disubstituted Hydantoins from Dipeptides and Unsymmetrical Ureas of Amino Acid Derivatives

“…From the synthetic point of view, these structures have been often reported as byproducts in peptide synthesis. − However, their structural and biological interests have given rise to the development of several methodologies for their preparation. The reaction of amino acid derivatives with isocyanates led to the formation of such hydantoins, after cyclization of the corresponding ureido derivatives in strong acidic conditions ,,, (Figure a). N -alkylation with halogeno acetates and their derivatives, ,,, and Michael addition reactions, allowed the introduction of the carboxyalkyl group at the N -3 position of hydantoins, with a particular interest in phenytoin derivatives ,− ,, (Figure b).…”

Rhodium-catalysed asymmetric hydrogenation as a valuable synthetic tool for the preparation of chiral drugs

“…Full conversion and very high enantioselectivity (98% ee) were obtained at catalyst loadings as low as 0.10 mol% (S/C = 1000), regardless of the rhodium complex used. The resulting hydrogenated product 33 is a valuable chiral building block for the preparation of the VLA-4 antagonist S9059, 94 which has exhibited potential as an antiinflammatory agent.…”

A Diversity-Oriented Approach to Spirocyclic and Fused Hydantoins via Olefin Metathesis

“…Imidazolidine-2,4-dione derivatives, generally called hydantoins, represent an important class of biologically active scaffolds that have broad applications in medicinal chemistry. , Several derivatives exhibit antidiabetic, antitumor, antiviral, antiulcer, antiarrythmic and antimuscarinic activities . In most cases, the biological activities arise from the different substituents that have been appended to the hydantoins. − In particular, spirohydantoins − and fused , bicyclic hydantoin derivatives have recently attracted much attention because they exhibit various biological activities. Some of these biologically active compounds are shown in Figure , which include naturally occurring spironucleoside hydantocidin (X = O) and its carbocyclic analogue (X = CH 2 ), spirocyclic core of biologically active alkaloids palau’amine and axinellamines, tetrantoin, tetrahydroisoquinoline-hydantoins .…”