Mini Reviews in Medicinal Chemistry - Volume 6, Issue 5, 2006

ACE Inhibitors (ACEI) and angiotensin receptor blockers (ARB) inhibit the renin-angiotensin system, but ACEI may do so incompletely when administered as monotherapy at conventional doses. In theory, combining an ACEI and ARB might be beneficial, whereas clinical evidence for this approach in hypertension is lacking. An ACEI-ARB combination is likely to be useful in proteinuric renal disease, but recent experimental evidence suggests that very high dose monotherapy with an ARB may be the best approach. However, the results of large outcome studies for combinations vs. ACEI or ARB monotherapy are still awaited.

Imiquimod is a synthetic imidazoquinoline heterocyclic amine of 240.3 Da (C14H16N4). Imiquimod is a cytokine inducer and a modifier of the innate immune response, as well as acquired antiviral and antitumor immune responses. Imiquimod 5% cream has proven to be an effective treatment for external genital warts, superficial basal cell carcinoma, and actinic keratosis.

Inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase (statins) are widely used for the prevention of atherosclerotic diseases. The effects of statins on the generation of reactive oxygen species (ROS) by in vitro and in vivo were studied. Administration of statins significantly decreased ROS generation in vitro and in vivo.

CD4+CD25+ T cells are essential for maintenance of self-tolerance and therefore have been referred to as regulatory T cells (Treg). Experimental tumor models revealed that Treg are potent inhibitors of an anti-tumor immune response. Treg are expanded in human cancer. Currently, a variety of strategies for the induction of a specific anti-tumor immune response are tested in preclinical and clinical settings. Biochemical strategies modifying and/or depleting Treg in cancer patients for an enhancement of vaccine-based therapeutic concepts will be discussed in detail in this review.

While most inhibitors of histone deacetylases (HDACs) are hydroxamic acid derivatives, several nonhydroxamates have recently been developed as inhibitors and attracted quite a deal of attention. In this review, we present the rational design, inhibitory effect and antiproliferative activity of non-hydroxamate HDAC inhibitors.

Hepatitis C virus represents a major global health problem, with approximately 3% of the world population infected. Immune-response modifiers represent the standard of care, given the lack of approved antiviral agents having direct activity against the viral proteins. Although in recent years, improvements in therapy have been attained by combined treatment with pegylated interferon and ribavirin, the discovery and development of next-generation small molecule and biologic agents is ongoing. Several of these newer therapeutics are focused on modulating Toll-like receptors, interferon-alpha signaling, and the pro-inflammatory cytokine balance. A comprehensive account of the lead compounds in development, the bioassays used for optimization of these immune response modifiers and their clinical status is presented.

This review focuses on the synthesis and mechanisms of antitumor activity of cationic nonphosphorus analogs of edelfosine. The role of variable length and mode of conjugation of the spacer group, the types of cationic 'head', and the length of the substituent at C(2) atom of the glycerol backbone are discussed, providing the basis for rational design of lipophilic anticancer drugs, in particular, for elimination of multidrug resistant cells.

Japanese traditional herbal medicine, which is known as "Kampo", has received increasing attention as an alternative approach to the treatment of various diseases. In order to safely and effectively apply Kampo, it is essential to understand oriental diagnostics. Herein, an outline of such diagnostics is introduced, and current trends in Kampo research are reviewed.

The causative agent of acquired immunodeficiency syndrome, HIV-1, depends on one of its enzymes, reverse transcriptase, to copy its single stranded RNA genome into a double stranded DNA nucleic acid suitable for integration in the host cell genome. In the last two decades, the advances in the knowledge of the kinetic mechanism of reverse transcription and in the determination of the crystallographic structures for the complexes of the enzyme with substrates and products were huge. However, all of this knowledge resulted in the design of RT inhibitors for which the virus, after a short period of exposure, becomes less susceptible, due to the development of resistance. The development of resistance is caused by the high frequency of viral mutation and the toxicity of those same drugs. Therefore, a closer look at all the available information might shed some light into this subject and help to develop new strategies to overcome the lack of long term clinical efficiency of these drugs. Here, we present a critical atomic level study of all the mutations that have been detected and reported so far, as a reaction of the enzyme to counteract the action of the inhibitors.

Drugs that block the entry of human immunodeficiency virus type 1 (HIV-1) into host cells abrogate the establishment of a productive infection and should ideally diminish the chances of HIV-1 developing resistance. This review will give an overview of the mechanism by which the envelope glycoprotein mediates HIV-1 entry and will summarize current drug developments.

Type 2 diabetes mellitus (T2DM) is highly prevalent chronic disease. Recently, many biological targets are discovered for treatment of this disease. The identification of the nuclear hormone receptor peroxisome proliferator activated receptors (PPAR) and their subtypes α, γ and δ or β as targets for controlling lipid, glucose and energy homeostasis has proved to be exciting. As hyperlipidaemia, obesity and insulin resistance are independent risk factors for coronary heart disease and macrovascular complications of diabetes; new agents that increase insulin sensitivity as well as decrease hyperlipidaemia by distinct yet complementary mechanism are being studied as they may provide improved therapy for T2DM and related disorders. In this article, we review highly potent PPAR agonists, PPARα / γ dual agonists, PPARγ pan agonists, alternative PPAR ligands like partial agonists or selective PPAR modulators (SPPARMs) and antagonists from a chemist point of view.

More recently, three novel purine nucleoside analogs, including clofarabine, nelarabine and immucillin H, have been introduced into clinical trials. These agents have different metabolic properties, novel mechanism of action, and are undergoing phase I-II clinical studies for the treatment of hematopoietic malignancies. Pharmacology and anticancer activity of PNA are the subjects of this review.

The plasma membrane calcium/calmodulin dependent ATPase (PMCA) is a calcium-extruding enzymatic pump important in the control of intracellular calcium concentration. PMCA is the only system for calcium extrusion in the majority of cells. In excitable cells such as cardiomyocytes however, PMCA has been shown to play only a minor role in calcium homeostasis. In these cells the main mechanism of calcium extrusion is the sodium calcium exchanger. However, increasing evidence points to an important role for PMCA in signal transduction; in particular in the nitric oxide signalling pathway. In this review we will discuss recent advances that support a key role for PMCA in signal transduction and the potential for therapeutic targeting of this molecule in the treatment of cardiac diseases.

Considerable information on the functions of prion protein (PrP) has been accumulated. One experimental approach is the use of PrP gene-knockout mice and derived cell lines. This approach has contributed to elucidating the functions of cellular prion protein (PrPC), such as its anti-oxidative and anti-apoptotic roles. This review will introduce the recent advances in prion biology made possible by the availability of these tools.

In this review, we show Angiotensin-(1-7) as a novel Renin Angiotensin System mediator that antagonizes cardiovascular and proliferative effects of Angiotensin II and exerts complex renal actions. We also speculate the possibility of new drugs for the treatment of cardiovascular, genitourinary and hepatic diseases by interfering with ACE2- Angiotensin-(1-7)-Mas axis.