Oral matrix metalloproteinase inhibitor marimastat
Marimastat (BB-2516) is an inhibitor of the family of enzymes known as matrix metalloproteinases (MMPs). These enzymes are considered to be primarily responsible for the degradation of extracellular matrix proteins in processes of tissue formation and remodelling. Under normal conditions the activity of MMPs is controlled at several levels, including their secretion as latent proenzymes and inhibition by endogenous tissue inhibitor of metalloproteinases (TIMPs). However, excessive MMP activity is now thought to play an important role in the pathogenesis of several diseases including cancer, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, neurodegenerative diseases [7], and cerebral haemorrhage. It is thought that MMP inhibitors may have utility in the treatment of some of these diseases.
The first two MMP inhibitors to be tested in patients were ilomastat (GM6001) and batimastat (BB-94). Neither compound showed good oral bioavailability and indications were sought that allowed alternative routes of administration. Ilomastat was administered as a topical agent in patients with corneal ulceration while batimastat was given as an intraperitoneal or intrapleural suspension in patients with malignant effusions. More recently, marimastat has been identified as one of the first MMP inhibitors to show good absorption following oral administration to animals. It is a broad spectrum reversible inhibitor of MMPs exhibiting IC50s of 5 nm, 6 nm, 3 nm, 16 nm, 230 nm and 5 nm against interstitial collagenase (MMP-1), gelatinase A (MMP-2), gelatinase B (MMP-9), matrilysin (MMP-7), stromelysin-1 (MMP-3) and metalloelastase (MMP-12), respectively.
Safety, pharmacology and toxicology studies suggest that marimastat has low oral and intravenous toxicity in animals. The only chronic target organ toxicity elicited has been inflammation of the tendons and joint ligaments of marmosets. On the basis of these preclinical data, it was thought that marimastat was a suitable compound to introduce into man with a view to further investigation of its role as an anti-cancer agent. The objectives of these first two studies were to assess the tolerability and pharmacokinetic profiles of single and continuous dosing of oral marimastat in healthy male volunteers.
Filed under: Clinical Pharmacology