Hexosaminidase inhibitors as new drug candidates for the therapy of osteoarthritis.
BACKGROUND
Articular cartilage from patients with osteoarthritis is characterized by a decreased concentration and reduced size of glycosaminoglycans. Degeneration of the cartilage matrix is a multifactorial process, which is due in part to accelerated glycosaminoglycan catabolism. Recently, we have demonstrated that hexosaminidase represents the dominant glycosaminoglycan-degrading glycosidase released by chondrocytes into the extracellular compartment and is the dominant glycosidase in synovial fluid from patients with osteoarthritis. Inhibition of hexosaminidase activity may represent a novel approach to the prevention of cartilage matrix glycosaminoglycan degradation and a potentially new strategy to treat osteoarthritis.


RESULTS
We have synthesized and investigated a series of iminocyclitols designed as transition-state analog inhibitors of human hexosaminidase, and demonstrated that the five-membered iminocyclitol 4 expresses the strongest inhibitory activity with K(i)=24 nM. Inhibition of hexosaminidase activity in human cultured articular chondrocytes and human chondrosarcoma cells with iminocyclitol 4 resulted in accumulation of hyaluronic acid and sulfated glycosaminoglycans in the cell-associated fraction. Similarly, incubation of human cartilage tissue with iminocyclitol 4 resulted in an accumulation of glycosaminoglycans in the pericellular compartment.


CONCLUSIONS
Inhibition of hexosaminidase activity represents a new strategy for preventing or even reversing cartilage degradation in patients with osteoarthritis.
Liu
J
J
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Shikhman
A R
AR
Lotz
M K
MK
Wong
C H
CH
D002358:Cartilage, Articular / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D019902:Chondrocytes / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D046508:Culture Techniques; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006025:Glycosaminoglycans / Q000378:metabolism; D006596:Hexosaminidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D007097:Imines / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D010003:Osteoarthritis / Q000188:drug therapy* / Q000201:enzymology; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000494:pharmacology; D013463:Sulfuric Acid Esters / Q000138:chemical synthesis / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D006025:Glycosaminoglycans; D007097:Imines; D011759:Pyrrolidines; D013463:Sulfuric Acid Esters; C013786:A73025; D006820:Hyaluronic Acid; D006596:Hexosaminidases