Matrix metalloproteinase inhibitor development and the remodeling of drug discovery.
Collagen turnover is a slow process on a biologic timescale with a t$\\frac12$ of 20-27 days that is mediated primarily by the matrix metalloproteinases (MMPs). Low collagen metabolism is not due to an intrinsically low Km of MMPs, but rather due to a highly regulated system of activity. Despite the stability of collagen and MMPs, the articles in this special addition illustrate the importance of this enzyme family in the disease process leading to congestive heart failure. Like MMPs, drug development is a tightly regulated process, and the successful turnover of MMP inhibitors into a marketed drug has also been a slow process on a pharmaceutical timescale. Since the discovery of the archetypal MMP (type 1 collagenase) over four decades ago by Gross and Lapierre, most major pharmaceutical companies have had MMP inhibitor programs for a variety of indications. Despite decades of research, tens of thousands of compounds synthesized and screened, and billions of dollars spent in clinical studies-Periostat (doxycycline hyclate, CollaGenex Pharmaceuticals Inc.) is the only collagenase inhibitor to be successfully launched. In addition, Periostat's approval is currently limited to periodontal disease. This article focuses on some of the lessons to be learned from the failure of so many MMP inhibitors across so many indications, and what potential exists for MMP inhibitors as a drug class, especially for heart failure.
Peterson
J Thomas
JT
Cardiovascular Pharmacology, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. tom.peterson@pfizer.com
D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004318:Doxycycline / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000032:analysis / Q000378:metabolism; D009140:Musculoskeletal Diseases / Q000139:chemically induced; D009206:Myocardium / Q000201:enzymology; D009369:Neoplasms / Q000188:drug therapy; D010510:Periodontal Diseases / Q000188:drug therapy
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D003094:Collagen; C100342:marimastat; D020782:Matrix Metalloproteinases; D004318:Doxycycline