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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Abstract

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.

ORCID iDs

Miller, Lisa M. ORCID logoORCID: https://orcid.org/0000-0002-0378-1071, Pritchard, John M., Macdonald, Simon J. F., Jamieson, Craig ORCID logoORCID: https://orcid.org/0000-0002-6567-8272 and Watson, Allan J. B.;
  • Item type:Article
    ID code:60317
    Dates:
    Date
    Event
    30 January 2017
    Published
    30 January 2017
    Published Online
    22 November 2016
    Accepted
    Notes: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
    Keywords:RGD integrins, therapeutic targets , tripeptide sequence, ligands, non-RGD-mimetic inhibitors, heterodimeric cell adhesion receptors, extracellular matrix, Chemistry, Chemistry(all)
    Subjects:Science > Chemistry
    Department:Faculty of Science > Pure and Applied Chemistry
    Strategic Research Themes > Health and Wellbeing
    Depositing user: Pure Administrator
    Date deposited:27 Mar 2017 15:44
    Last modified:05 Jun 2023 13:39
    Related URLs:
    URI:https://strathprints.strath.ac.uk/id/eprint/60317
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