Current Medicinal Chemistry - Volume 18, Issue 5, 2011

For the last twenty years, significant progress in Molecular and Cellular Biology has resulted in a better characterization and understanding of the biology and prognosis of acute myeloid leukemia (AML). These achievements have provided new opportunities for the development of innovative, more effective therapies. Novel agents potentially useful in the treatment of patients with AML include new formulations of established drugs, newer nucleoside analogs, molecular target drugs, monoclonal antibodies and other agents. Three newer nucleoside analogs, clofarabine, troxacitabine and sapacitabine have been recently investigated in patients with AML. Two methylation inhibitors, 5-azacyticline and decitabine are pyrimidine nucleoside analogs of cytidine which can be incorporated into RNA and/or DNA. Lower doses of these agents are active in AML and have been extensively investigated, especially in secondary AML and AML in elderly patients. Tipifarnib and lonafarnib are orally available farnesyltransferase inhibitors with in vitro and in vivo activity against AML. In recent years, FLT3 inhibitors, lestaurinib, tandutinib and PKC 412 have been developed and tested in AML. The preclinical observations and clinical studies indicate that FLT3 inhibitors are promising agents in the treatment of FLT3 mutated AML patients, especially when used in combinations with chemotherapy. Several newer MDR inhibitors, including valspodar (PSC-833) and zosuquidar trihydrochloride have been also tested for the treatment of relapsed AML. This article reviews the various classes of AML targets and drugs that are under early phase clinical evaluation, especially those that are likely to enter clinical practice in the near future.

CYP2C9 metabolizes more than 100 clinically used drugs including phenytoin, S-warfarin, tolbutamide, glipizide, diclofenac, and losartan with varying contributions. CYP2C9 is considered one of the most important CYPs, with substrate specificity typical of many new chemical entities (i.e. lipophilic bases). A large interindividual variation has been identified for the CYP2C9 activity and for the clinical response to the therapeutics metabolised by the enzyme. So far, at least 33 variants of CYP2C9 (*2 through to *34) have been identified. CYP2C9 is one of the clinically significant drug metabolising enzymes that demonstrates genetic variants with significant phenotype and clinical outcomes. This review updates our current knowledge on the polymorphic metabolism of drugs by CYP2C9 and discusses its implications in drug development. The authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Genetics Abstracts (CSA), SCOPUS, Chemical Abstracts, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase (all from inception to October 31 2010). A comprehensive literature search has identified 32 drugs that are subject to CYP2C9-mediated polymorphic metabolism. Drugs that are subject to polymorphic metabolism with clinical significance include nine nonsteroidal anti-inflammatory agents, six sulfonylurea antidiabetic drugs and, most critically, three oral coumarin anticoagulants. Polymorphisms in CYP2C9 have the potential to affect the clearance and clinical response of CYP2C9 substrate drugs with low therapeutic indices such as warfarin, phenytoin, and certain antidiabetic drugs. Warfarin has served as a model drug of how pharmacogenetics can be employed to achieve maximum efficacy and minimum toxicity. Minimizing interindividual variability in drug exposure due to CYP2C9 polymorphisms is an important goal in drug development and discovery.

The aim of this paper is to review the latest data on the pharmacological modulation of asymmetric dimethylarginine in human disease. When the terminal nitrogens of the guanidine portion of an arginine become methylated through the action of N-methyl transferases, two chemically close, but physiologically different amino acids are synthesized: symmetric and asymmetric dimethylarginine. The vascular origin of asymmetric dimethylarginine and its inhibitory activity on endothelial nitric oxide synthase give it an important role in certain diseases in which microcirculation is compromised: hypertension, atherosclerosis, inflammatory bowel disease, and diabetes. This review discusses the role that asymmetric dimethylarginine plays in the development of vascular disease, and, wherever possible, evaluates its use in clinical diagnosis. The fact that a number of chemically unrelated drugs, such as angiotensin II antagonists, selective beta- 1 adrenergic antagonists, plant phenolics, statins, and farnesoid X receptor agonists have all been found to reduce dimethylarginine levels in plasma or tissue allows for an integrated study. Although it is difficult to determine exactly why these various agents all have the same effect on arginine metabolism, an explanation of their mechanisms of action is needed. We have thus analyzed the mechanisms involved and reviewed potential trends in the therapeutic use of these drugs.

With the continuing epidemics of obesity and diabetes, nonalcoholic fatty liver disease (NAFLD) has received increased attention. Great efforts are being undertaken to improve the noninvasive diagnosis of NAFLD, with the ultimate goal of optimizing treatment options and clinical outcomes. Research suggests that blood-borne biochemical markers can be used to distinguish simple steatosis from nonalcoholic steatohepatitis (NASH), thus reducing the need of liver biopsy. Future developments in the field of diagnostic biochemistry within the spectrum of NAFLD can make this approach ideal for screening and monitoring purposes. In this review, we provide an overview of the different blood-borne markers which have been recently proposed for differentiating simple steatosis from NASH. We will also consider the practical and statistical issues that seem to be limiting the effective integration of biomarkers into clinical development.

During the past two decades, the incidence of invasive fungal infections has been increasing dramatically. Clinical available antifungal agents have several drawbacks such as limited potency and spectrum, drug related toxicity, non-optimal pharmacokinetics, and severe resistance. There is an emergent need to develop new antifungal drugs with novel chemical structures and novel mechanism of action. This review will focus on the most significant achievements in the discovery of antifungal lead structures within last few years. In particular, we pay more attention on the structureactivity relationship of antifungal leads and provide perspectives for future antifungal drug discovery.

Neglected helminthic diseases cause many social, economic and health care challenges in developing countries. The high number of patients suffering from these parasitic infections and the lack of sufficient treatment options represent severe problems. Research on new drugs and therapies to meet this urgent requirement has to be intensified. This review focuses on infections caused by four helminthic parasites, which have been declared as neglected diseases by the World Health Organization: namely drancunculiasis, lymphatic filariasis, onchoceriasis, and schistosomiasis. They show a considerable overlap in their world-wide prevalence and treatment strategies. Nevertheless, treatment is not without complications. The most efficient lymphatic filariasis drug, diethylcarbamazine, causes severe adverse effects in onchocerciasis patients and completely fails in the treatment of drancunculiasis. In this review, we discuss these incongruities at the molecular and cellular level. Furthermore, established or investigational drug combination regimens are highlighted. In the past years, progress has been made in the area of schistosomiasis and onchocerciasis. The molecular biology of underlying mechanisms, signalling pathways and related targets affected by drug therapy are discussed in detail. Finally, successful treatment strategies and remaining future challenges are summarized.