Discovery of 3-OH-3-methylpipecolic hydroxamates: potent orally active inhibitors of aggrecanase and MMP-13.

A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group that binds in the S1' pocket. These compounds also possess markedly improved bioavailability and lower metabolic clearance compared to analogous 3,3-dimethyl-5-hydroxypipecolic hydroxamates.

Pyran-containing sulfonamide hydroxamic acids: potent MMP inhibitors that spare MMP-1.

The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P1' groups is described. The compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the series contain either a monocyclic or bicyclic pyran ring adjacent to the hydroxamate group.

Cartilage damage after intraarticular exposure to collagenase 3.

Objective: To determine the in vivo effects of intraarticular MMP-13.

Methods: Human recombinant MMP-13 was injected intraarticularly (i.a.

Detection of collagenase-induced damage of collagen by 9A4, a monoclonal C-terminal neoepitope antibody.

To determine whether the collagen network is compromised by collagenase during acute inflammation, a monoclonal antibody (9A4) was developed with specificity for the C-terminal neoepitope sequence generated by collagenase-cleavage of type II collagen (Gly-Pro-Pro-Gly-Pro-Gln-Gly-COOH). 9A4 was shown to detect the collagen collagenase-cleavage neoepitope with a K = 1.7 x 10(-7) M (type II) and K = 2 x 10(-6) M (type I).

Exercise protects against articular cartilage degeneration in the hamster.

Objective: It has been reported that osteoarthritis can occur in hamsters. The present study was undertaken to determine the effects of exercise on the composition of articular cartilage and synovial fluid and on the development of cartilage degeneration in these animals.

Methods: Young (2.