Mmps

Heart Failure Reviews, 9, 63–79, 2004 C 2004 Kluwer Academic Publishers. Manufactured in The Netherlands

Matrix Metalloproteinase Inhibitor Development and the Remodeling of Drug Discovery
J. Thomas Peterson
Cardiovascular Pharmacology, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA

Abstract. Collagen turnover is a slow process on a biologic timescalewith a t 1 of 20–27 days that is mediated primar2 ily 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 congestiveheart 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 ofindications. 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 belearned 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. Key Words. matrix metalloproteinase inhibitor, MMP, collagenase, drug discovery, drug development, attrition, heart failure

Introduction
ICI (now AstraZeneca) is attributed as initiating the search for an orally bioavailablesmall molecule matrix metalloproteinase (MMP) inhibitor in the late 1970’s for the treatment of arthritis [1]. The project was driven by the hypothesis that MMP inhibition would slow or reverse the remodeling events (collagen degradation) causing arthritis rather than acting primarily as a palliative [2]. Since the seminal work at ICI, there has been an expansion in the number of known MMPs toover 26 identified enzymes [3], as well as potential therapeutic indications (rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease, metastatic tumorogenesis and neoplastic growth, aneurysm, atherosclerosis, and heart failure). Drug discovery also changed substantially during this period, moving from a reliance

on bioassay screens (e.g., reduction in cartilage degradation by MMPinhibitors [4,5]) to the use of recombinant enzymes [6,7]; utilization of chombichem arrays [8], NMR [9], and computational chemistry [10,11] to accelerate rationale drug design; the advent of mass screening to identify hits [12]; the use molecular biology both to identify new targets [13] and provide confidence in rationale; the development of in silico pharmacokinetic profiling [14] and cell basedsystems to assess pharmacokinetics and in vitro toxicology screens [15]; the recognition that biomarkers can greatly enhance the chance of successful drug development [16–18]; and the quantum leap in development costs [19] and perceived risk [20]. Continued investment in MMP inhibitor development has been sustained despite increased costs and a growing litany of failed clinical trials (Table 1) bythe potential market for developing a new drug class useful in the life-long treatment of rheumatoid or osteoarthritis, metastatic tumor and neoplastic growth, osteoporosis, periodontal disease, aneurysm, atherosclerosis, and/or heart failure. Compelling MMP inhibitor efficacy in animal models has also maintained interest among medical and pharmaceutical researchers. What then has stymied the...