- Development of new hydroxamate matrix metalloproteinase inhibitors derived from functionalized 4-aminoprolines
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A series of hydroxamates was prepared from an aminoproline scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for five enzymes within the MMP family, and a number of inhibitors, such as compound 47, display broad-spectrum activity with sub-nanomolar potency for some enzymes. Modifications of the P1′ portion of the molecule played a key role in affecting both potency and selectivity within the MMP family. Longer-chain aliphatic substituents in this region of the molecule tended to increase potency for MMP-3 and decrease potency for MMP-1, as exemplified by compounds 48-50, while aromatic substituents, as in compound 52, generated broad-spectrum inhibition. The data is rationalized based upon X-ray crystal data which is also presented. While the in vitro peroral absorption seemed to be less predictable, it tended to decrease with longer and more hydrophilic substituents. Finally, a rat model of osteoarthritis was used to evaluate the efficacy of these compounds, and a direct link was established between their pharmacokinetics and their in vivo efficacy.
- Natchus,Bookland,De,Almstead,Pikul,Janusz,Heitmeyer,Hookfin,Hsieh,Dowty,Dietsch,Patel,Garver,Gu,Pokross,Mieling,Baker,Foltz,Peng,Bornes,Strojnowski,Taiwo
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p. 4948 - 4963
(2007/10/03)
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- Design, synthesis, and biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold
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The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp2 center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically 3 hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated.
- Cheng, Menyan,De, Biswanath,Almstead, Neil G.,Pikul, Stanislaw,Dowty, Martin E.,Dietsch, Charles R.,Dunaway, C. Michelle,Gu, Fei,Hsieh, Lily C.,Janusz, Michael J.,Taiwo, Yetunde O.,Natchus, Michael G.,Hudlicky, Tomas,Mandel, Martin
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p. 5426 - 5436
(2007/10/03)
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