Peter Raddatz

Synthesis and biological evaluation of integrin antagonists containing trans- and cis-2,5-disubstituted THF rings.

The synthesis of a series of RGD mimetics is described. All compounds consist of a central 2,5-disubstituted tetrahydrofuran core, a variable linker to a guanidino group, and a beta-amino alanine unit to mimic the carboxylic acid. Three types of linkers were investigated: a simple four-atom methylene chain (type A, compounds 14, 15, 16, and 17), a four-atom methylene chain with an additional chiral center, and a nitrogen substituent (type B, compounds 38, 39, and 40), and an amide linker of different length with an additional chiral center (type C, compounds 59, 60, 61, and 62). A variety of compounds were tested as potential integrin antagonists in a receptor binding assay (alphaIIbbeta3, alphavbeta3, and alphavbeta5). The relative and absolute configuration of the chiral centers at the THF ring had a pronounced effect on the binding activity and selectivity. Compound 14 proved to be a selective inhibitor of alphaIIbbeta3 (IC50=20nM), whereas compound 40 exhibited high activity for binding of alphaIIbbeta3 (IC50=67nM) and alphavbeta3 (IC50=52nM).

New antithrombotic RGD-mimetics with high bioavailability

Abstract A new class of antithrombotic RGD-mimetics with a novel axazolidinonemethyl scaffold was synthesized. High oral activity and bioavailability was found in this series of compounds.

Synthesis and biological evaluation of dianhydrohexitol integrin antagonists

Abstract The synthesis of a series of RGD mimetics is described. All compounds have a 1,4:3,6-dianhydrohexitol core, a variable linker to a guanidino group, and a serine ether to mimic the carboxylic acid. Two types of linkers were combined with 1,4:3,6-dianhydro-D-sorbitol (1 – 4) and with 1,4:3,6-dianhydro-L-iditol (5). The five compounds were tested as potential integrin antagonists in a receptor binding assay (αIIbβ3, αvβ3, and αvβ5 type). Receptor binding activities in the μmol range were observed.

New peptidomimetics in the chemistry of fibrinogen receptor antagonists

RGD-peptidomimetics are currently being investigated as a class of potential antithrombotics that antagonize the fibrinogen receptor, GP IIb/IIIa, on the surface of platelets. These mimetics are expected to have decisive advantages-such as higher activity and specificity, oral bioavailability and longer duration of action-over known antithrombotics. For further optimization in this respect, novel peptidomimetic GP IIb/IIIa antagonists with an oxazolidinonemethyl central building block were synthesized. This building block proved to be very versatile as an ‘anchor’ for structurally different C-termini and was the starting point for highly efficient and orally active compounds.

Review Cardiovascular & Renal; Recent Developments in Glycoprotein llb/llla Antagonists

Platelet adhesion and aggregation, which have been identified as promising targets for the development of antithrombotic drugs, are mediated by a family of glycoprotein receptors. Antagonists of the most important of these receptors, Gpllb/llla, are currently under investigation for a range of both cardiovascular and cerebrovascular disorders. This article aims to compare data for existing Gpllb/llla antagonists in various stages of clinical development, with those compounds which appear in the recent patent literature.