Discovery of novel Cobactin-T based matrix metalloproteinase inhibitors via a ring closing metathesis strategy

The discovery of potent N-hydroxyl caprolactam matrix metalloproteinase (MMP) inhibitors (6) based on the natural product Cobactin-T (2) is described. The synthetic method, which utilizes the ring closing metathesis reaction, is compatible to provide complementary (R) and (S) enantiomers. These compounds tested against MMP-2 and 9, show that the R stereochemistry (i.e., 16), which is opposite for that found in the natural product Cobactin-T is >1000-fold more active with IC50 values of 0.2–0.6 nM against both enzymes. The variation in the incorporation of the sulfonamide enzyme recognition element (Ar2XAr1SO2N(R1), 6), along with alterations in the RCM/double bond chemistry (R2) provided a series of sub nanomolar MMP inhibitors. For example, compounds 16 and 34 were found to be the most potent with IC50 values against MMP-2 and MMP-9 found to be between 0.2 and 0.6 nM with 34 being the most potent compound discovered (MMP-2 IC50 = 0.39 nM and MMP-9 IC50 = 0.22 nM). Compounds 16 and 34 showed acceptable drug-like properties in vivo with compound 34 showing oral bioavailability.

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