Mini Reviews in Medicinal Chemistry - Volume 4, Issue 7, 2004

Understanding disease mechanisms at a molecular level and designing or discovering appropriate molecular entities through this understanding is an important approach to modern drug discovery. Ligands that can inhibit biochemical targets such as enzymes or receptors are specially important in this regard. Over 30% of drugs currently used are the inhibitors of enzymes and other receptors. This issue of Mini-Reviews in Medicinal Chemistry contains several good articles, contributed by leading experts on biological inhibitors. The review by Rossi and Zavalloni describes the progress made in the development of inhibitors of glycoprotein IIb / IIIa (GP IIb / IIIa) receptor, which is involved in platelet aggregation. Reszka and Rodan have reviewed the role of nitrogen-containing biophosphonate in the prevention of spinal and non-vertebral osteoporotic fractures, involving the inhibition of a key biosynthetic enzyme, farnesyl diphosphate synthase, which catalyzes the synthesis of 15-carbon isoprene moiety, farnesyl disphosphate. The isoprene moiety plays an important role in the biosynthesis of several regulatory proteins involved in the bone-resorbing osteoclast inhibition of serine proteases of eukaryotic and prokaryotic origins, which has been reviewed by Konaklieva and Plotkin. Serine proteases are involved in a variety of health disorders, such as pulmonary hypertension, destruction of the lung parenchyma in emphysema, as well as in resistance of bacteria to β-lactam antibiotics. A review by Miljkovic et al. focuses on the inhibition of nitric oxide synthase by mycophenolic acid. NO is synthesized from Larginine by intracellular enzyme NO synthase, while NO- is involved in immune response of an organism and in a multitude of other biochemical functions. Abell et al. have presented various inhibitors developed in recent years against types I and II 3- dehydroquinate dehydratase enzymes involved in shikimate and quiate pathways. Guerrero and Rosell in review the contribution of enzyme inhibitors in biorational approaches for pest control: another important application of enzyme inhibition strategy. These targeted enzymes are involved in normal physiology and reproduction of insect pests, and their disruption effects the life cycle of insects. ŧren et al. review the properties of matrix metalloproteinases and their role in the pathogenesis of intestinal anastomotic dehiscence. This review also contains a wealth of information about synthetic metalloproteinase inhibitors. Along with this three other general reviews have also been included in this issue of MRMC. It is hoped that these reviews from leading authorities will be of great interest to medicinal chemists as well as to researchers involved in drug development and discovery programs of pharmaceutical industries and R & D institutions.

The glycoprotein IIb / IIIa (GP IIb / IIIa) receptor is the most important receptor involved in platelet aggregation. A stable GP IIb / IIIa inhibition is required when a massive platelet activation triggers thrombosis. Three GP IIb / IIIa inhibitors are currently approved for clinical use: abciximab, tirofiban and integrilin. Their different pharmacodynamic and pharmacokinetic properties reflect a different efficacy in platelet inhibition.

The current paradigm for drug discovery requires the identification of a target involved in the disease process (e.g. enzyme or receptor) and the development of an appropriate ligand (activator, inhibitor or selective modulator). Selection of ligands for clinical development is based on the therapeutic window between efficacy vs. safety and ADME (absorption, distribution, metabolism and elimination) considerations. For bisphosphonates (BPs) the process has not followed that paradigm. BPs have very low absorption and are retained in bone, their target tissue. A few have been used on a limited basis for over 20 years in diseases of rapid bone destruction (e.g. post-menopausal osteoporosis, Paget's disease, bone metastases, etc.), without understanding their molecular mechanism of action. The nitrogen-containing BPs (N-BPs) are the latest and most potent addition to this family of compounds and have the widest use. They have high potency, are specifically targeted to the osteoclast on bone and are used at very low doses (5-10 mg clinically). Over the last four years, there was significant progress in elucidating the mechanism of action of BPs, both lacking and containing nitrogen. This review will focus on the mechanism of action of the N-BPs, specifically alendronate (ALN) and risedronate (RIS), the two agents most widely used. For these and all other N-BPs, the molecular target is the isoprenoid biosynthetic enzyme, farnesyl diphosphate synthase, in the cholesterol biosynthesis pathway. Although inhibition of this enzyme by N-BPs results in the suppression of sterol biosynthesis, it is actually disruption of a branch pathway, isoprenylation, that is responsible for N-BP pharmacological activity. Isoprenylation involves covalent linkage of the 15 or 20 carbon isoprene moiety farnesyl diphosphate or geranylgeranyl diphosphate, respectively, to the carboxy-terminus of regulatory proteins, including the small GTPases Ras, Rac, Rho and Cdc42. The latter three, as well as numerous others, are geranylgeranylated and play a rate-limiting role in the activity of the bone-resorbing osteoclast. This targeted osteoclast inhibition accounts for the potency of the N-BPs and for their ability to elicit the desired therapeutic response of suppressing bone turnover. The occasional gastrointestinal irritation caused by N-BPs appears to be mechanism-based and is also briefly reviewed.

The ability to inhibit serine proteases is a major focus in the pharmaceutical industry. Serine proteases of medical importance range in phylogenetic diversity from the metallo-proteases, which play a role in pulmonary hypertension, and destruction of the lung parenchyma in emphysema, to those proteases (betalactamases), which play a role in the resistance of bacteria to beta-lactam antibiotics. In both the mammalian and microbial systems, the development of serine protease inhibitors has been a focal strategy spurring investigations in the area of serine protease dependent prodrugs that incorporate a bactericidal moiety as well as other classes of metalloprotease inhibitors.

The focus of this review is the influence of an immunosuppressive xenobiotic drug mycophenolic acid on the induction of nitric oxide production in various cell types. The potential therapeutic significance of the cell-specific fine-tuning of nitric oxide release by mycophenolic acid, as well as the mechanisms behind the drug action are discussed.

Inhibitors of varying potency have been developed for types I and II 3-dehydroquinate dehydratase (dehydroquinase), enzymes from the shikimate and quinate pathways that catalyse the dehydration of dehydroquinate to dehydroshikimate. These inhibitors have resulted from enzyme mechanistic studies and from the direct search for enzyme inhibitors with herbicidal, fungicidal or antimicrobial potential. This review discusses the design of the various inhibitors that have been produced so far and some structure-activity relationships. The majority of these inhibitors are based on dehydroquinate analogues, although some work has also been carried out on dehydroshikimate and bissulfonamides. Some discussion is also presented on advances in the synthesis of these types of compounds.

Conventional insecticides of broad spectrum have been widely used as the main tools for controlling insect pests. However, as the consequence of their toxicity and deep environmental impact, new biorational, and more specific approaches have been developed. In this review we present an overview of those pest control approaches which have resulted from studies dealing with inhibition of the enzymes involved in the physiology, growth, molting, development and reproduction of insect pests. These approaches involve synthetic compounds from laboratory studies and natural chemicals present in the crop plants. Recent developments using inhibitors expressed in transgenic plants are also outlined.

Excessive matrix metalloproteinase activities have been implicated in the pathogenesis of intestinal anastomotic dehiscence, a serious and potentially life-threatening complication following gastrointestinal surgery. In this review, the properties of matrix metalloproteinases are summarized followed by presentation of clinical therapeutic interventions with synthetic matrix metalloproteinase inhibitors and novel experimental data on colon anastomosis repair that warrant exploration of these drugs in surgical colorectal patients.

Recent advances in structure determination and computational methods have encouraged the development of structure-based virtual screening. Here we survey progress in the field and review the most recent methods, validation experiments and real applications, including an in-house example of hit identification for the oncology target Hsp90. These results provide a basis for discussing the current state of structure-based virtual screening and to outline the developments that are expected to have a major impact in the near future.

Organofullerene derivatives have shown a great potential in a wide variety of biological activities such as DNA photocleavage, HIV-protease inhibition, neuroprotection and apoptosis. Among the plethora of functionalized organofullerenes that have been synthesized, fullerene-based amino acids are particularly appealing for structural studies and biological applications. When the fullerene-framework is incorporated into peptides, its original properties can be substantially modified. In addition, the water-solubility of the fullerene derivatives is enhanced, which makes such molecules amenable to biological studies. In this review, recent advances in the growing field of medicinal chemistry of fullerene derivatives will be discussed. Emphasis will be given to the synthesis of the biggest unnatural amino acid 3,4-fulleroproline (Fpr) and its derivatives. For example, Fpr derivatives have been found to interact with different hydrolytic enzymes and selectively discriminate between rationally designed peptides. Fullerene-based peptides have been found to substantially activate enzymes involved in the oxidative deamination of biogenic amines. In addition, their membranotropic properties and effects on the structure and permeability of the lipid bilayer of phosphatidylcholine liposomes as well as the transmembrane transport of bivalent metal ions have been studied. Finally, applications in medicinal chemistry of such types of amino acids and peptides will be highlighted.