TY - JOUR
T1 - Emergence of small molecule non-RGD-mimetic inhibitors for RGD integrins
AU - Miller, Lisa M.
AU - Pritchard, John M.
AU - Macdonald, Simon J. F.
AU - Jamieson, Craig
AU - Watson, Allan J. B.
N1 - This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.6b01711
PY - 2017/1/30
Y1 - 2017/1/30
N2 - 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.
AB - 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.
KW - RGD integrins
KW - therapeutic targets
KW - tripeptide sequence
KW - ligands
KW - non-RGD-mimetic inhibitors
KW - heterodimeric cell adhesion receptors
KW - extracellular matrix
UR - http://pubs.acs.org/journal/jmcmar
U2 - 10.1021/acs.jmedchem.6b01711
DO - 10.1021/acs.jmedchem.6b01711
M3 - Article
SN - 0022-2623
VL - 60
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 8
ER -