Emergence of small molecule non-RGD-mimetic inhibitors for RGD integrins

Miller, Lisa M. and Pritchard, John M. and Macdonald, Simon J. F. and Jamieson, Craig and Watson, Allan J. B. (2017) Emergence of small molecule non-RGD-mimetic inhibitors for RGD integrins. Journal of Medicinal Chemistry, 60 (8). ISSN 0022-2623 (https://doi.org/10.1021/acs.jmedchem.6b01711)

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The RGD integrins are recognized therapeutic targets for thrombosis, fibrosis, and cancer, amongst others. Current inhibitors are designed to mimic the tripeptide sequence (arginineglycine-aspartic acid) of the natural ligands; however, the RGD-mimetic antagonists for αIIbβ3 have been shown to cause partial agonism, leading to the opposite pharmacological effect. The challenge of obtaining oral activity and synthetic tractability with RGD-mimetic molecules, along with the issues relating to pharmacology, has left integrin-therapeutics in need of a new strategy. Recently, a new generation of inhibitor has emerged that lacks the RGD-mimetic. This 2 perspective will discuss the discovery of these non-RGD-mimetic inhibitors, and the progress that has been made in this promising new chemotype.