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

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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:13 Sep 2021 02:20
      Related URLs:
      URI:https://strathprints.strath.ac.uk/id/eprint/60317
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