Zinc-binding groups modulate selective inhibition of MMPs

ChemMedChem
Arpita AgrawalSeth M Cohen

Abstract

The need for selective matrix metalloproteinase (MMP) inhibition is of interest because of the range of pathologies mediated by different MMP isoforms. The development of more selective MMP inhibitors (MMPi) may help to overcome some of the undesired side effects that have hindered the clinical success of these compounds. In an effort to devise new approaches to selective inhibitors, herein we describe several novel MMPi and show that their selectivity is dependent on the nature of the zinc-binding group (ZBG). This is in contrast to most current MMPi, which obtain isoform selectivity solely from the peptidomimetic backbone portion of the compound. In the present study, six different hydroxypyrone and hydroxypyridinone ZBGs were appended to a common biphenyl backbone and the inhibition efficiency of each inhibitor was determined in vitro (IC(50) values) against MMP-1, -2, -3, -7, -8, -9, -12, and -13. The results show that the selectivity profile of each inhibitor is different as a result of the various ZBGs. Computational modeling studies were used to explain some trends in the observed selectivity profiles. To assess the importance of the ZBG in a biological model, two of the semiselective, potent MMPi (and one control) were ...Continue Reading

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Citations

Nov 5, 2010·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Kevin B DanielSeth M Cohen
Sep 1, 2009·Chemical Reviews·Kathryn L Haas, Katherine J Franz
Dec 30, 2010·Journal of Medicinal Chemistry·Jennifer A JacobsenSeth M Cohen
Oct 1, 2013·Journal of Medicinal Chemistry·Joshua A Day, Seth M Cohen
Jan 28, 2009·Journal of Medicinal Chemistry·Arpita AgrawalSeth M Cohen
May 8, 2010·Chemical Communications : Chem Comm·Jody L Major Jourden, Seth M Cohen
Feb 4, 2011·Dalton Transactions : an International Journal of Inorganic Chemistry·Matthieu Rouffet, Seth M Cohen
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May 29, 2010·Journal of the American Chemical Society·Matthieu RouffetSeth M Cohen
Sep 16, 2008·Bioorganic & Medicinal Chemistry·Dimitris Georgiadis, Athanasios Yiotakis
Dec 10, 2008·ChemMedChem·Monika JagodzinskaMatteo Zanda
Jul 31, 2008·Chembiochem : a European Journal of Chemical Biology·Faith E JacobsenSeth M Cohen
Aug 10, 2013·ChemMedChem·Christian PerezSeth M Cohen
May 14, 2011·Chemical Biology & Drug Design·Sherida JohnsonMaurizio Pellecchia
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Jun 23, 2011·Archiv der Pharmazie·Maria Teresa RubinoPaolo Tortorella
Aug 18, 2010·Angewandte Chemie·Jody L Major Jourden, Seth M Cohen
Jan 9, 2010·ChemMedChem·Arpita AgrawalSeth M Cohen
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Aug 29, 2009·Biochimica Et Biophysica Acta·Jennifer A JacobsenSeth M Cohen
Jun 23, 2015·Genes & Diseases·Jillian CathcartJian Cao

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