Current Topics in Medicinal Chemistry, Volume 4, No. 12, 2004
Contents
Bioorganic Chemical Approaches for the Design of Protease
Inhibitors
Guest Editor: Dong H. Kim
Recent
Developments in the Design of Mechanism-based and Alternate Substrate
Inhibitors of Serine Proteases Pp.1203-1216
Jiaying Zhong and William C. Groutas
Chemistry-based
Design of Inhibitors for Carboxypeptidase A Pp.1217-1226
Dong H. Kim
Quest for
Selectivity in Inhibition of Matrix Metalloproteinases Pp.1227-1238
Stephen Brown, Samy O. Meroueh, Rafael Fridman and
Shahriar Mobashery
Inhibitors of
3C Cysteine Proteinases from Picornaviridae Pp.1239-1253
Manjinder S. Lall, Rajendra P. Jain and John C. Vederas
Matrix Metalloproteinase Inhibitors
Guest Editor: Jeremy I. Levin
The Evolution of
the Matrix Metalloproteinase Inhibitor Drug Discovery Program at Abbott
Laboratories Pp.1255-1267
Carol K. Wada
Sulfonamide-Based
Acyclic and Conformationally Constrained MMP Inhibitors: From Computer-Assisted
Design to Nanomolar Compounds Pp.1269-1287
Stephen Hanessian and Nicolas Moitessier
The Design and
Synthesis of Aryl Hydroxamic Acid Inhibitors of MMPs and TACE Pp.1289-1310
Jeremy I. Levin
The Application
of X-ray, NMR, and Molecular Modeling in the Design of MMP Inhibitors Pp.1311-1327
Thomas S. Rush III1, and Robert Powers
Abstracts
[Back to top] Recent
Developments in the Design of Mechanism-based and Alternate Substrate
Inhibitors of Serine Proteases
Jiaying Zhong and William C. Groutas
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 agents and/or pharmacological probes to gain a better understanding of the pathophysiology of a particular disease. This review focuses on recent developments related to the design of mechanism-based and alternate substrate inhibitors of serine proteases of mammalian and non-mammalian origin. Numerous examples are cited that illustrate the fundamental principles and subtleties associated with the design of covalent and non-covalent inhibitors of these enzymes. This is an exciting and promising area of investigation that will undoubtedly continue unabated in the future.
[Back to top] Chemistry-based
Design of Inhibitors for Carboxypeptidase A
Dong H. Kim
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 molecule inactivators that inhibit the enzymic activity of CPA irreversibly by chemically modifying a functional group at the active site of the enzyme. Of these irreversible inhibitors mechanism-based inactivators are of special interest due to their high selectivity for target enzyme and long duration of enzyme inhibition. These inactivators have been designed rationally on the basis of established topology of the active site and catalytic mechanism of the enzyme. Chemistry inherent to the zinc ion at the active site of the enzyme has been exploited in the design. The present review covers the progress in the CPA inactivator design strategy. The design strategy developed with CPA may be transferred to other zinc proteases of medicinal interest, leading to discovery of a novel type of therapeutically useful enzyme inhibitors.
[Back to top] Quest for
Selectivity in Inhibition of Matrix Metalloproteinases
Stephen Brown, Samy O. Meroueh, Rafael Fridman and
Shahriar Mobashery
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, these inhibitors have not met the promise and expectations in clinical trials. The broad-spectrum inhibition, which besides MMPs often targets other metalloproteinases, has been considered one of the potential problems that affects the therapeutic efficacy of MMPs inhibitors. Several MMP inhibitors that show selectivity for various MMPs have been reported in the past few years. This report describes the structural and inhibitory properties of these novel inhibitors, which hold considerable promise for effective targeting of these important enzymes.
[Back to top] Inhibitors of 3C
Cysteine Proteinases from Picornaviridae
Manjinder S. Lall, Rajendra P. Jain and John C. Vederas
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 precursor protein and is crucial for viral maturation and replication. Although it is a cysteine proteinase, this 3C enzyme has a topology similar to those of the chymotrypsin-like serine proteinases. A series of inhibitors of HAV and HRV 3C proteinases were synthesized and tested as potential lead compounds for the design of therapeutic agents for human picornaviral pathogens. This research shows that thiol-reactive groups or “warheads” such as iodoacetamides, b-lactones, Michael acceptors, ketones and pseudoxazolones can be used as effective tools to inhibit the HAV and HRV 3C proteinase enzymes. In addition, studies based on enzyme-inhibitor kinetics, mass spectrometry and NMR spectroscopy were effectively used to gain knowledge concerning enzyme-inhibitor mechanism of action and enzyme-inhibitor regiospecific reactivity.
[Back to top] The Evolution of
the Matrix Metalloproteinase Inhibitor Drug Discovery Program at Abbott Laboratories
Carol K. Wada
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 hydroxamate MMP inhibitors. The metabolic instability of the biaryl hydroxamates led to the discovery of a new class of N-formylhydroxylamine (retrohydroxamate) biaryl ethers, exemplified by ABT-770 (16). Toxicity issues with this pre-clinical candidate led to the discovery of another novel class of retrohydroxamate MMP inhibitors, the phenoxyphenyl sulfones such as ABT-518 (19j). ABT-518 is a potent, orally bioavailable, selective inhibitor of MMP-2 and 9 over MMP-1 that has been evaluated in Phase I clinical trials in cancer patients.
[Back to top] Sulfonamide-Based
Acyclic and Conformationally Constrained MMP Inhibitors: From Computer-Assisted
Design to Nanomolar Compounds
Stephen Hanessian and Nicolas Moitessier
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 automated and reliable docking program, we embarked on the design and synthesis of enantiopure inhibitors incorporating cyclic scaffolds. This ultimately led to compounds exhibiting inhibitory activities in the nanomolar range. Interestingly, the qualitative ranking prediction was found to be in good agreement with the observed activities.
[Back to top] The Design and
Synthesis of Aryl Hydroxamic Acid Inhibitors of MMPs and TACE
Jeremy I. Levin
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 in the study of the physiological role of these enzymes. Furthermore, the different selectivity profiles offered by these MMP/TACE inhibitors may allow the determination of which metalloprotease, or group of metalloproteases, must be inhibited for the safe, long-term treatment of osteoarthritis, rheumatoid arthritis and cancer. Some of these compounds have demonstrated useful biological activity in efficacy models relevant to osteoarthritis and rheumatoid arthritis and are therefore potential clinical candidates.
[Back to top] The Application of X-ray, NMR, and Molecular
Modeling in the Design of MMP Inhibitors
Thomas S. Rush III1, and
Robert Powers
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 TNFa-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.