Current Topics in Medicinal Chemistry - Volume 4, Issue 12, 2004

Proteases play crucial roles for the normal functioning of biological systems. Proteins that are generated in ribosome must be degraded in order for them to carry out their functions in the biological systems and these protein degradations are catalyzed by a variety of proteolytic enzymes. A myriad of metabolic reactions involved in diverse physiological processes such as protein turnover, digestion, blood coagulation and wou Read More

The matrix metalloproteinases (MMPs) are a family of more than 20 zinc-dependent mammalian enzymes, both membrane bound and secreted, most of which are involved in the cleavage of some component of the extracellular matrix (ECM), including collagen and gelatin. Related enzyme families include the adamalysins (ADAMs) and the ADAM-TS enzymes. The discovery of these important enzymes and their physiological Read More

A wide range of human diseases are associated with the aberrant activity of mammalian, viral, bacterial or parasitic proteases. These include members of all four classes of proteases, namely, serine, cysteine, aspartic and metalloproteases. The involvement of proteases in disease states has provided the impetus behind studies related to the design of potent and selective inhibitors and their use as either therapeutic agent Read More

Carboxypeptidase A (CPA) is one of the most extensively studied zinc proteases and serves as a prototypical enzyme for a large family of metalloproteases that play important roles in biological systems. CPA has been used as a model enzyme for developing design strategies of inhibitors that restrain the catalytic activity of zinc proteases. Recently, there has been made a remarkable progress in designing small Read More

Matrix metalloproteinases (MMPs), of which at least 26 are known in humans, have been linked to a number of pathological conditions including tumor metastasis, inflammation, neurological and cardiovascular diseases. Inhibition of MMPs has been widely sought as a strategy in intervention of these disease processes. Whereas a large number of broadspectrum MMP inhibitors have been developed over the past decade, thes Read More

The Picornaviridae are among the smallest icosahedral positive-sense single stranded RNA containing viruses known, and comprise one of the largest and most important families of human and animal pathogens. The hepatitis A virus (HAV) and human rhinovirus (HRV) are important pathogens that belong to the picornavirus family. All picornaviruses have a 3C proteinase that processes an initially biosynthesized precu Read More

Matrix metalloproteinases (MMPs) have been implicated in several pathologies. At Abbott Laboratories, the matrix metalloproteinases inhibitor drug discovery program has focused on the discovery of a potent, selective, orally bioavailable MMP inhibitor for the treatment of cancer. The program evolved from early succinate-based inhibitors to utilizing in-house technology such as SAR by NMR to develop a novel class of biaryl hydr Read More

The present account relates to our studies in the computer assisted design and synthesis of acyclic and cyclic MMP inhibitors. Our early efforts focused on the preparation of cyclopropane and tetrahydrofuran-based mimics of batimastat which were not active. The discovery of subnanomolar sulfonamide-based acyclic inhibitors instigated the design of novel target compounds. Thus, with the help of a fully autom Read More

Three different classes of aryl hydroxamic acid scaffolds have been explored and provided potent inhibitors of MMP-1, -2, -9, -13 and TACE. Structure-based design has allowed the evolution of these inhibitors from broad spectrum inhibitors into compounds that are more selective for MMPs relevant to particular disease states. Aryl hydroxamates selective for MMP-9, MMP-13 and TACE have been disclosed that may aid Read More

The following review discusses the successful application of X-ray, NMR, and molecular modeling in the design of potent and selective inhibitors of matrix metalloproteinases (MMPs) and TNFα-converting enzyme (TACE) from Wyeth. The importance of protein and ligand mobility as it impacts structure-based design is also discussed. The MMPs are an active target for a variety of diseases, including cancer and arthritis.