Current Medicinal Chemistry (v.20, #14)

RNAi in Clinical Studies by P. Kubowicz, D. Zelaszczyk, E. Pekala (1801-1816).
RNA interference (RNAi) is an efficient process of posttranscriptional gene silencing. In recent years it hasbeen developed into a new technology in biopharmaceutical fields of science. RNAi products include short interferenceRNA (siRNA) but also short hairpin RNA (shRNA), bifunctional short hairpin RNA (bi-shRNA) and microRNA(miRNA). They combine with homologous fragments of the mRNA and cause its degradation. It results in inhibition ofprotein synthesis, or in mutation in the gene encoding it. RNAi has been used in analysis of genomes and creation of newanimal models to test drugs. From the pharmaceutical point of view, what is the most important is its therapeutic application.So far the basic and clinical research has been focused on the following targets: macular degeneration, cancer and antiviraltherapy. But there are also reports on clinical trials in asthma, hypercholesterolemia and genetic diseases such asinherited skin disorders and amyloidosis. Among over 20 therapeutics that reached clinical trials, only few are still investigated.Another few are clinical candidates. The review focuses on RNAi products under clinical evaluation and theirmost promising new applications.

Chronic stable angina pectoris (CSAP) is the most common manifestation of coronary artery disease (CAD).Angina pectoris occurs as a result of an imbalance between myocardial perfusion and the demands of the myocardium.Elevated heart rate (HR) is an important pathophysiological variable that increases myocardial oxygen demand, and alsolimits tissue perfusion by reducing the duration of diastole during which most myocardial perfusion occurs. Elevated restingHR represents a significant predictor of all-cause and cardiovascular mortality in the general population and patientswith cardiovascular disease (CVD) because it assists the progression of CVD through the development of atherosclerosis,plaque destabilization, and initiation of arrhythmias. Since &#946;-blockers have been found to reduce HR, therefore, they arecurrently viewed as the first line therapy for CSAP and are associated with an improved prognosis after acute myocardialinfarction (AMI) or congestive heart failure (CHF). The classical treatments for HR reduction have shown negative aspects,such as &#946;-blockers therapy which exerts negative effects on regional myocardial blood flow and function when HRreduction is eliminated by atrial pacing. Calcium channel antagonists functionally antagonize coronary vasoconstrictionmediated through &#945;-adrenoreceptors, and are thus devoid of this undesired effect, but the compounds are neverthelessnegative inotrope. Ivabradine (IVA), a pure HR lowering drug, reduces the demand of myocardial oxygen during exercise,contributes to the restoration of oxygen balance and is therefore benefitial in chronic CVD. No relevant negative effectshave been observed on cardiac conduction, contractility, relaxation, repolarization or blood pressure (BP). Beneficial effectsof IVA have been noticedin CSAP and CHF, with optimal tolerability profile due to selective interaction with I<sub>f</sub>channel of sino atrial node cells. More recently, IVA has been highly recommended to be used in patients with CAD inassociation with &#946;-blockers. This review highlights the importance of IVA in the treatment of ischemic heart disease.

Insight into the Medicinal Chemistry of the Endocannabinoid Hydrolase Inhibitors by C.N. Kapanda, J.H. Poupaert, D.M. Lambert (1824-1846).
Endocannabinoid hydrolases are nowadays increasingly considered as potential therapeutic targets for treatingseveral pathological states. So far, numerous classes of endocannabinoid hydrolase inhibitors have been described. Weherein review the medicinal chemistry of these inhibitors with a particular emphasis on the basis of their design, chemicalstructure, structure-activity relationships, and inhibition mechanisms.

Emerging Role of Colloidal Drug Delivery Systems (CDDS) in NSAID Topical Administration by Carmelo Puglia, Giorgia Tirendi, Francesco Bonina (1847-1857).
NSAIDs are the most commonly prescribed category of drugs for the treatment of musculoskeletal pain and inflammationassociated with many conditions. Topical administration of these drugs is always the best choice since adverseeffects occur commonly with systemic NSAID therapy.Colloidal drug delivery systems (CDDS) are interesting systems, which are able to improve the duration of drug residencein the skin and to allow an achievable drug sustained and controlled release compared to conventional topical formulations.This review focuses on micro and nanoemulsions, vesicular carriers and nanoparticles as novel high efficiency deliverysystems of NSAIDs in topical applications.

Histone Deacetylase Inhibitors: An Attractive Strategy for Cancer Therapy by Jiyang Li, Guangqiang Li, Wenqing Xu (1858-1886).
Histone deacetylases are able to catalyze the hydrolysis of N-acetyl lysine residues of histones which packagechromosomal DNA. Therefore they play an important role in mediating gene expression and cell proliferation. HDAC inhibitorshave not only shown promise as antiparasitic, antineurodegenerative, antirheumatologic agents and immunosuppressant,but as potent anticancer agents by inducing cell cycle arrest, differentiation and apoptosis. This review highlightsrecent development in design, synthesis and biological evaluation of HDAC inhibitors for cancer therapy.

Peptide Based Macrocycles: Selective Histone Deacetylase Inhibitors with Antiproliferative Activity by H. Rajak, A. Singh, P.K. Dewangan, V. Patel, D.K. Jain, S.K. Tiwari, R. Veerasamy, P.C. Sharma (1887-1903).
Histone deacetylase inhibitors (HDACi) have been enthusiastically investigated as a novel generation of chemotherapeuticsfor cancers usually called as epigenetic therapeutics. Histone deacetylases have been found to influencecellular function by catalyzing the removal of acetyl groups from &epsilon;-N-acetylated lysine residues of several protein substratesincluding histones, transcription factors, &alpha;-tubulin, and nuclear importers. Cyclic peptides represent the most structurallycomplicated and diverse class of histone deacetylase inhibitors. Each subtype of the Histone Deacetylase (HDAC)family perform a distinct role in the gene expression and cyclic peptides with their plentiful set of surface contacts, zincbinding group and macrocyclic cap, can target enzyme precisely through adequate modulation of the amino acid configurationaland structural assortment. The present article summarizes current status of different peptide based macrocycliccompounds being developed as HDACi for the treatment of cancer.

For some time Photodynamic Therapy and electrochemotherapy have been used as alternative therapies againstskin cancer. The primary aim of this work was to develop, characterize, and evaluate the in vitro cytotoxic activity of newdrug delivery systems based on chitosan nanoparticles containing aminolevulinic acid derivatives such as prodrug (5-ALAand its ester derivative 8-ALA). The second goal of this study was to evaluate the synergistic effect of a combination ofclassical Photodynamic Therapy and electrochemotherapy, which is routinely utilized to modulate and enhance thepermeation of photosensitizers, prodrugs, and other active compounds through the skin, improving the efficiency of PDTin the treatment of cutaneous neoplasms.

Immunophilins are Involved in the Altered Platelet Aggregation Observed in Patients with Type 2 Diabetes Mellitus by E. Lopez, A. Erro, J.M. Hernandez-Cruz, G.M. Salido, P.C. Redondo, J.A. Rosado (1912-1921).
Platelet hyperaggregability might contribute to vascular complications associated with type 2 diabetes mellitus(DM2).Experimental evidence supports a direct link between altered Ca2+ entry and hyperaggregability in DM2 patients.Objectives: We aimed to investigate whether altered immunophilin expression and function are involved in the abnormalCa2+ entry observed in platelets from DM2 patients. Results: Inhibition of immunophilins by tacrolimus (FK506) and sirolimus(rapamycin) reduced Ca2+ entry in platelets from healthy donors and DM2 patients. Similarly, immunophilin inhibitorsreduced platelet degranulation in both healthy and DM2 subjects. Nevertheless, &#945;-granule secretion reduction wasgreater than that observed for dense granules in platelets from DM2 patients. However, no difference was observed in theinhibition of secretion in platelets from healthy subjects. Additionally, altered expression of FK506 binding protein-52(FKBP52) and coupling to Ca<sup>2+</sup> channels were found in platelets from DM2 patients compared to healthy subjects. Finally,reduction in platelet function from healthy subjects and DM2 patients in the presence of immunophilin antagonistswas observed, being this dysfunction more evident in platelets from DM2 patients. Conclusions: We suggest that, amongothers, FKBP52 expression and function are altered in platelets from DM2 patients, contributing to the altered Ca<sup>2+</sup> entryand hyperaggregability in these cells.