Medicinal Chemistry Reviews - Online (Discontinued) - Volume 1, Issue 4, 2004

Clinical transplantation relies on our ability to chemically immunosuppress graft recipients without overt toxicity over a lifetime. The four areas of immunotherapy: (induction, basic maintenance, adjuvant and steroid therapy) have been available since the beginning of surgically successful transplantation almost 50 years ago. The development of new immunosuppressants continues to focus on these areas. Induction immunotherapy developments include the use of humanized antibodies, specific targets (basiliximab, daclizumab) and lymphocyte depletion (anti-thymocyte globulin, campath-1H). Promising results from pilot trials allow for subsequent low dose maintenance monotherapy. New inhibitors of calcineurin isoforms (ISATx247) may disassociate the anti-rejection effect from the toxicity of conventional calcineurin inhibitors. Revived investigation of older anti-proliferative or anti-metabolite drugs (rapamycin, mycophenolic acid, leflunomide) show promise in preventing B-cell responses and reducing chronic rejection but development of derivatives (everolimus, mycophenolate mofetil, ERL 080, MNA 279, MNA 715) may have a stronger commercial than experimental basis. Trials of steroid immunotherapy have focused on steroid elimination but trial of newer locally active steroids may be beneficial.

The hydroxamic acid moiety plays an important role as a pharmacophore in a variety of biologically active agents. Such agents include enzyme inhibitors, anticancer agents, antimicrobial compounds, and agents used in the treatment of cardiovascular diseases, to name but a few. The following is an updated review of the basic medicinal chemistry and pharmacology of hydroxamic acids derivatives.

Trichoderma and Gliocladium species are ubiquitous soil dwellers, capable of utilising a wide variety of substrates and of rapid growth. They are found in diverse ecological niches including marine and freshwater environments associated with plants and animals. They are prolific producers of secondary metabolites many of which show biological activity against infective agents. This update describes progress in the topic since the original review and covers the period from mid-2000 to October 2003.

Acridines have been used as chemotherapeutic agents against bacteria, protozoa and fungi, and they now find important use as anticancer drugs. There is a paucity of crystal structures of acridine-DNA complexes above the dinucleotide level, but recent structures of acridinecarboxamide topoisomerase II poisons complexed to hexanucleotides have allowed a molecular rationalisation of their structure-activity relationships for cytotoxicity and for their kinetics of DNA binding.

Human telomerase is a ribonucleoprotein enzyme complex that, when expressed at high level, enables cells to maintain telomere length, allowing indefinite replicative capacity. The notion that telomerase is reactivated in 80-90% of human cancers has led to the proposal of telomerase as a promising therapeutic target for novel anticancer interventions. In this review an update regarding antisense-based approaches used thus far to inhibit telomerase activity in human cancer cells is provided. All these strategies significantly inhibited the enzyme's catalytic activity in several experimental tumour models. However, while in some studies tumour cell growth arrest was observed as a consequence of telomere shortening after prolonged telomerase inhibition, other studies have shown that antisense-based treatments targeting telomerase induced rapid loss (i.e. within a few days) of tumour cell viability with concomitant apoptosis. These findings have conferred to telomerase a putative pro-survival and anti-apoptotic role, which would be independent from its telomereelongating activity and rely on telomere capping function of the enzyme. However, the role of telomerase in tumourigenesis, beyond the classical mechanism of telomere lengthening, needs to be further investigated to provide a better rationale for the use of antitelomerase-based therapies in clinical trials.

Multidrug resistance (MDR) is a type of resistance to structurally unrelated chemotherapeutic drugs, and is one of the main obstacles in the chemotherapy of cancer, malaria and other diseases. In the case of cancer, its inhibition by combination of chemosensitizers with antitumor compounds continues to be a very active field of research, since the availability of safe and potent reversal agents would be very beneficial for clinical use. The discovery of new structures with MDR modulating properties is taking place at a fast pace, together with the clinical evaluation of the most promising of the previously known compounds. Most modulators act by binding to membrane transport proteins (specially P-gp and MRP) and inhibiting their drug-effluxing activity, but some of them act by indirect mechanisms, including inhibition of the expression of the mdr1 gene. General structureactivity studies of this therapeutic group are hampered by the very heterogeneous chemical structure of the compounds, although some conclusions regarding the location of binding domains of P-gp and the structural requirements for MDR reversal have been drawn recently.

Prednisone alone or a lower dose of prednisone in combination with azathioprine induces remission and enhances survival in autoimmune hepatitis. Treatment failure, incomplete response, drug-induced side effects, and relapse after drug withdrawal are unsatisfactory outcomes that justify the search for new therapies. Potent new drugs promise greater blanket immunosuppression than current regimens, and insights into the pathogenic mechanisms of the disease make site-specific interventions possible. Cyclosporine and tacrolimus are calcineurin inhibitors that impair the transcription of interleukin 2, reduce the expression of cytokines, and diminish T lymphocyte proliferation. Mycophenolate mofetil antagonizes the synthesis of purines and depletes stores of guanine nucleotides necessary for DNA synthesis and expansion of T cell clones. Controlled clinical trials are warranted to establish the role of these new drugs in the treatment of autoimmune hepatitis. Promising site-specific therapies include peptides that competitively block autoantigen presentation, agents such as cytotoxic T lymphocyte antigen-4 that inhibit the second co-stimulatory signal of immunocyte activation, T cell vaccination, oral tolerance therapy, cytokine manipulation with monoclonal antibodies and recombinant supplements, gene therapy, and hepatocyte-targeted therapeutics. Confident animal models of experimental autoimmune hepatitis are necessary to mature these interventions. In conclusion, promising immunosuppressive agents that alter cytokine expression and T lymphocyte proliferation may be of value in the treatment of autoimmune hepatitis. Critical mechanisms of immunocyte activation, cytotoxic T cell expansion, and cytokine modulation are the targets of site-specific interventions.

In 2000, Wyeth disclosed that 4-(3-bromoanilino)-6,7-dimethoxy-3-quinolinecarbonitrile was a potent and selective EGFR kinase inhibitor. Subsequent reports showed that variation of the substituents on the 4-anilino group of the 3-quinolinecarbonitrile core changed the kinase specificity from EGFR to either Src or MEK. This article is an update of a 2002 review that summarized Wyeth's efforts in the area of 4-anilino-3-quinolinecarbonitrile kinase inhibitors. Since then, Wyeth has reported the SAR of EKB-569, an irreversible EGFR inhibitor currently in clinical trials. Variation of the 4-anilino group of EKB-569 provided HKI-272, a dual inhibitor of EGFR and HER-2. In addition, the 3- quinolinecarbonitrile analogs of known quinazoline EGFR inhibitors were prepared. SKI-606, initially reported to be a Src inhibitor, was found to also inhibit Abl kinase and therefore could be a potential alternative treatment to Gleevec. SKI-606 was also efficacious in a rat model of stroke. Additional Src kinase inhibitors, including some tricyclic analogs, were obtained by variation of the substituent at C-7. Finally, 3-quinolinecarbonitrile MEK inhibitors with potent cell activity were identified.

Plasmodium falciparum, the causative agent for the most lethal form of malaria, has developed resistance to almost all widely used antimalarials. Availability of the genome sequence with mRNA expression and proteome profiles permit identification of new therapeutic targets, opening up fresh possibilities for drug and vaccine development. Complete absence of the de novo purine biosynthetic pathway from the parasite genome makes all enzymes of the salvage pathway targets worthy of study for inhibitor design. Success of folate antagonists in antimalarial therapy provides impetus for detailed examination of other enzymes involved in pyrimidine biosynthesis. This review examines recent biochemical and structural data on enzymes of these two pathways. The salient features of the parasite purine nucleoside phosphorylase, hypoxanthine guanine phosphoribosyltransferase, adenylosuccinate synthetase and dihydrofolate reductase -thymidylate synthase are presented.

Infection with the obligate intracellular bacterial pathogen Chlamydia pneumoniae is emerging as a risk factor in cardiovascular diseases. Evidence supporting a role for C. pneumoniae in atherosclerosis comes from epidemiologybased, pathology-based, cell-culture, and animal model studies, as well as from several clinical trials. Specific chlamydial virulence determinants, most notably chlamydial lipopolysaccharide (cLPS) and chlamydial heat shock protein 60 (cHsp60), have been identified and may contribute to atherogenesis by either serving as antigens or through directly activating key cell types to induce inflammatory cascades. This short review serves to update the reader on new data implicating cHsp60 and other putative chlamydial components in atherogenesis.

He development of biological agents has provided rheumatologists with a variety of new and effective treatment options. The success of these agents in the treatment of rheumatoid arthritis, has spurred research into novel targets for the management of other rheumatic diseases. In addition to rheumatoid arthritis, TNF-α inhibitors (infliximab and / or etanercept) have been approved for the use in patients suffering from Crohn's disease, ankylosing spondylitis and psoriatic arthritis. Also the treatment of persistent monoarticular and oligoarticular arthritis, resistant to disease modifying antirheumatic drugs and steroid therapies, with intra-articular anti-TNF therapy appears promising. Most importantly, such therapies have improved the quality of life and clinical outcomes in this group of patients. This article reviews the recent clinical studies published and ongoing research on the treatment of rheumatic diseases, other than rheumatoid arthritis, using these biological agents.

The recent developments in the field of osteoporosis have opened a new era in the management of the disease and warrant a similar change in our therapeutic paradigms. After being one of medicine's most untreatable disorders, osteoporosis is following the steps of hypertension being amenable to treatment through defining the patients most likely to develop fractures; and better assessment of their prognosis for defining the most appropriate intervention thresholds. This review will highlight the new concepts published about fracture prediction and how risk factors can be incorporated into the algorithm to determine the absolute risk of a patient having a fracture. Also the results from recently published clinical trials about the novel therapeutic approaches for treatment of osteoporosis, such as the first bone forming agent parathyroid hormone; the potent antiresorptive agent zoledronate, as well as agents such as statins and strontium ranelate that are currently under investigation, and were found able to dissociate between reduced bone resorption and increase bone formation offering a perspective on their role in fracture prevention and treatment of osteoporosis. Lastly this article will discuss the yet unanswered question; will the dream of combination therapy be true?