title: Discovery of novel Cobactin-T based matrix metalloproteinase inhibitors via a ring closing metathesis strategy.
abstract: 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 0.2-0.6nM 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 0.6nM with 34 being the most potent compound discovered (MMP-2 IC(50)=0.39nM and MMP-9 IC(50)=0.22nM). Compounds 16 and 34 showed acceptable drug-like properties in vivo with compound 34 showing oral bioavailability.
authors.affiliation: High-Throughput Synthesis and Neurological Disorders Teams, Johnson & Johnson Pharmaceutical Research & Development, 920 Route 202, Raritan, NJ 08869, USA. wilsonlarr@gmail.com
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Wilson
authors.forename: Bingbing
authors.initials: B
authors.lastname: Wang
authors.forename: Shyh-Ming
authors.initials: SM
authors.lastname: Yang
authors.forename: Robert H
authors.initials: RH
authors.lastname: Scannevin
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Burke
authors.forename: Prabha
authors.initials: P
authors.lastname: Karnachi
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Rhodes
authors.forename: William V
authors.initials: WV
authors.lastname: Murray
mesh_terms: D001381:Azepines / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D003500:Cyclization; D055808:Drug Discovery; D020128:Inhibitory Concentration 50; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D001381:Azepines; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; C524936:cobactin T