Recent non-hydroxamate matrix metalloproteinase inhibitors

Abstract

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endo-peptidases that have the capacity to degrade all elements of the extracellular matrix (ECM) and are required for homeostatic maintenance of the ECM. Interest in MMPs arose from the accumulating evidence implying that over-activity of MMPs plays a role in mediating or accompanying a diverse array of pathologies. Because of this, there has been an ongoing, and alas unsuccessful, effort for nearly two decades to develop clinically applicable MMP inhibitors (MMPIs) as drugs. The largest family of the inhibitor candidates that failed in clinical trials is that of hydroxamic acids. This review i) attempts to rationalise the failure of hydroxamates as MMPIs, ii) critically reviews publications and patents of the last few years, which report new non-hydroxamate based MMPIs, and iii) summarises factors that are considered important for success in developing clinically useful MMPIs.

• allosteric
• antiangiogenic
• anti-invasive
• arthritis
• atherosclerosis
• cancer
• cartilage degradation
• chelator
• chronic obstructive pulmonary disease (COPD)
• collagenase
• coronary artery disease
• extracellular matrix (ECM)
• hydroxamic acid
• inflammation
• inhibitor
• metastasis
• matrix metalloproteinase (MMP)
• MMP inhibitor (MMPI)
• myocardial infarction
• osteoarthritis
• periodontal disease
• remodelling
• rheumatoid arthritis
• X-ray crystallography