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 consi st of a central 2,5-disubstituted tetrahydrofuran core, a variable linker t o a guanidino group, and a beta-amino alanine unit to mimic the carboxylic acid. Three types of linkers were investigated: a simple four-atom methylen e 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, comp ounds 38, 39, and 40), and an amide linker of different length with an addi tional chiral center (type C, compounds 59, 60, 61 and 62). A variety of co mpounds were tested as potential integrin antagonists in a receptor binding assay (alpha(IIb)beta(3), alpha(v)beta(3), and alpha(v)beta(5)). The relat ive and absolute configuration of the chiral centers at the THF ring had a pronounced effect on the binding activity and selectivity Compound 14 prove d to be a selective inhibitor of to be a selective inhibitor of to be a sel ective inhibitor of alpha(IIb)beta(3) (IC50 = 20nM), whereas compound 40 ex hibited high activity for binding of alpha(IIb)beta(3) (IC50 = 67 nM) and a lpha(v)beta(3) (IC50 = 52 nM).