Aggrecanase: The Family and Its Inhibitors

Abstract

Osteoarthritic joint disease is characterized by the progressive loss of articular cartilage resulting in functional impairment, pain and discomfort. The major components in cartilage, collagen and aggrecan, are lost during disease through the action of degradative proteolytic enzymes. The proteases responsible for aggrecan degradation are termed aggrecanases. The aggrecanases represent a family of enzymes with great therapeutic potential as targets for the treatment of osteoarthritis. Here we review the family of aggrecanases and the progress made toward the identification of potent and selective enzyme inhibitors for use as therapeutic agents.

Recent Research Advances in Selective Matrix Metalloproteinase‐13 Inhibitors as Anti‐Osteoarthritis Agents

“…Piperidine sulfonamide 12 featured with a reverse hydroxamate, the N ‐hydroxyformamide, as a ZBG (Figure ) . It potently inhibited MMP‐13 (IC 50 =1.6 n m ), aggrecanase‐1 (ADAM‐TS4), aggrecanase‐2 (ADAM‐TS5), and other drug targets for intervention in OA . Compound 12 showed little inhibition on MMP‐1 (9700 n m ) and weak activity against MMP‐14 (180 n m ).…”

“…In addition, 13 was free of hERG activity up to 50 μ m and was found not to be mutagenic. It also demonstrated safety in rat 28‐day toxicity studies . Owing to its excellent activity, selectivity, DMPK properties in preclinical trials, 13 was progressed as drug candidate for the treatment of OA by AstraZeneca as AZD6605.…”

Advances in the development of novel aggrecanase inhibitors

“…Aggrecan is a multidomain proteoglycan that provides the elasticity and compressive resistance to the articular cartilage that is lost in the initial phases of OA. This loss of aggrecan fragments via proteolysis is attributable to aggrecanase activity [2]. If this degradation is not halted or reversed, the cartilage will be subject to further breakdown by additional metalloproteases resulting in irreversible damage to the joint.…”