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

作者：Wilson Lawrence J^*; Wang Bingbing; Yang Shyh Ming; Scannevin Robert H; Burke Sharon L; Karnachi Prabha; Rhodes Kenneth J; Murray William V

来源：Bioorganic & Medicinal Chemistry Letters, 2011, 21(21): 6485-6490.

DOI：10.1016/j.bmcl.2011.08.068

• Matrix metalloproteinases
• Ring closing metathesis
• MMP-2
• MMP-9
• Cobactin-T

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 IC(50) values of 0.2-0.6 nM against both enzymes. The variation in the incorporation of the sulfonamide enzyme recognition element (Ar(2)XAr(1)SO(2)N(R(1)), 6), along with alterations in the RCM/double bond chemistry (R(2)) provided a series of sub nanomolar MMP inhibitors. For example, compounds 16 and 34 were found to be the most potent with IC(50) 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 IC(50) = 0.39 nM and MMP-9 IC(50) = 0.22 nM). Compounds 16 and 34 showed acceptable drug-like properties in vivo with compound 34 showing oral bioavailability.

• 出版日期2011-11-1