Pharmacological characterisation of a tool αvß1 integrin small molecule RGD-mimetic inhibitor.

ABSTRACT

Compound 8 is a selective αvß1 small molecule inhibitor that has been used in pre-clinical studies to identify and characterise the αvß1 integrin as a potential target in fibrotic disease. In this study we further investigated the selectivity and pharmacokinetics of compound 8 to determine a link between the levels of αvß1 engagement required to achieve in vivo pharmacodynamic efficacy. The selectivity of compound 8 for the arginyl-glycinyl-aspartic acid and ß1 integrins was measured using purified integrin protein preparations in radioligand binding studies with both labelled ([3H]compound 8) and unlabelled versions. The pharmacokinetic profile of compound 8 was completed in in vitro blood protein binding assays and in in vivo studies using male C57BL/6 mouse following i.v. dosing. The high selectivity of compound 8 for αvß1 over the other αv integrins was confirmed, however a reduced selectivity was demonstrated for the ß1 integrin family, with high affinity observed for α4ß1 (comparable to αvß1), moderate affinity for α2ß1, α3ß1 and α8ß1, and low affinity for α5ß1 and α9ß1. Compound 8 was shown to be cleared quickly from the blood with a short half-life of 0.5 h. In conclusion, the data in this study suggest that compound 8 has the potential to engage a number of integrins in vivo beyond αvß1, that raises a degree of uncertainty regarding its mechanism of action in models of fibrotic disease.