Structure–activity relationship of a series of non peptidic RGD integrin antagonists targeting α5β1: Part 1

Abstract

Potent antagonists of the integrin α(5)β(1), which are RGD mimetics built from tyrosine are described. This letter describes the optimization of in vitro potency obtained by variation of two parts of the molecule, the basic group and the linker between the basic group and the phenyl central core.

Integrin α5β1, the Fibronectin Receptor, as a Pertinent Therapeutic Target in Solid Tumors

“…Interestingly, new orally available α5β1 integrin antagonists were described recently by this pharmaceutical group [142,143]. Other small non peptidic molecules were synthesized by AstraZeneca and showed some selectivity for α5β1 integrin compared to αvβ3 integrin [144,145]. …”

The Functions and Applications of RGD in Tumor Therapy and Tissue Engineering

“…The guanidine function of arginine is engaged in a bidentate salt bridge with a highly conserved aspartic acid residue in the α subunit of the receptor. The carboxylate group of the aspartic acid coordinates with the metal-ion dependent adhesion site; the adhesion site is located in β subunit of the receptor [18]. …”

Synthesis and Evaluation of the Aldolase Antibody-Derived Chemical-Antibodies Targeting α5β1 Integrin

“…There are numerous potent anti-α5β1 integrin inhibitors 27,28,29,30 that could be modified with a linker and conjugated to Ab 38C2 giving anti-α5β1 chem-Abs. Initially, we focused on compound 1 27 (Figure 1), and synthesized an analogous compound 2 that possessed an alkyne function for introducing a linker enroute the Ab-PAs, 4 ’s, and chem-Abs 38C2- 4 ’s.…”

“…There are numerous potent anti-α5β1 integrin inhibitors − that could be modified with a linker and conjugated to Ab 38C2 giving anti-α5β1 chem-Abs. Initially, we focused on compound 1 (Figure ) and synthesized an analogous compound 2 that possessed an alkyne function for introducing a linker en route to the Ab-PAs, 4 s, and chem-Abs 38C2- 4 s. The linker site in compound 2 was established based upon the structure–activity relationship data around compound 1 and our prior studies with the anti-αvβ3 and αvβ5 chem-Abs. ,,− Conjugation of compound 2 into Ab 38C2 binding sites could be mediated through a series of bifunctional linkers 3 , which are different from each other only in length and that possess an azide group.…”