Current Medicinal Chemistry - Volume 16, Issue 33, 2009

Cholesterol ester transfer protein (CETP) plays a significant role in high density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT). A reduction in CETP activity leads to an increase in HDL-cholesterol levels. However, the relationship between reduced CETP function and atherosclerosis is complex and confusing. In the hypertriglyceridemic state, CETP is highly expressed and RCT leads to the formation of small dense low density lipoprotein (LDL) and small dense HDL, both of which are involved in the progression of atherosclerosis. Significant associations of the B1B1 genotype with higher plasma CETP concentration and/or CETP activity and lower HDL cholesterol were reported in several, but not all, studies. The magnitude of postprandial lipemia is also associated with plasma CETP concentration and lipoprotein content and size. Several conditions such as metabolic syndrome, hypertension, insulin resistance, obesity and familial hypercholesterolaemia are characterized by a more pronounced postprandial hypertriglyceridemia and delayed TG clearance than normal states. Thus, CETP is considered as a candidate target for drug therapy. A number of synthetic CETP inhibitors (CGS25159 and JTT-705) were evaluated in animals with satisfactory results. In humans, two CETP inhibitors were evaluated, JTT-705 and torcetrapib, leading to HDL increase. However, torcetrapib administration was associated with an increase in blood pressure and other “off-target” effects. It is also not clear whether the HDL produced during treatment with torcetrapib is bioactive (i.e. an “on target” undesirable action). In the current review, CETP function regarding lipid metabolism (in fasting and fed states) from human and animal studies as well as the current knowledge on CETP inhibitors are discussed. We also discuss gender influence on the action of hypolipidemic drugs and their effect on CETP mass and activity, as well as on the lipid profile.

Anticancer drugs are essential agents in the global strategy developed to fight cancer. Still, narrow therapeutic indices, erratic pharmacokinetics profiles and lack of selectivity towards malignant tissues often hamper their efficacy at the bedside, when they not cause severe toxicities. In this respect, developing innovative drug delivery strategies that would selectively target malignant tissues is still an ongoing story, both in experimental and in clinical oncology. Delivery systems such as liposomes are usually required when an existing formulation is not satisfactory, because encapsulation is expected to provide higher therapeutic efficacy and safety. Such significant improvement in therapeutic efficacy and/or therapeutic indices has already been achieved in patients with some liposome-encapsulated drugs such as anthracyclines. It is now possible to develop a wide range of vectors varying in size, composition, and surface morphology suitable for a variety of therapeutic applications, including for targeting tumor tissues. Reformulation of anticancer drugs in liposomes remains a challenging opportunity to stretch the therapeutic indices of many cytotoxic drugs, through the optimization of their distribution in the body. Despite these promising and exciting perspectives in oncology, to date only few drugs (e.g., anthracyclines) have actually made their way as liposomes from the bench to the bedside. However, as target therapies have brought a new hope in the cancer war in the 2000's, developing now targeted delivery systems is more and more seen as the next step to further improve clinical outcome in cancer patients. This review covers the achievements, limits, and new expectancies of anticancer drugs as candidates for liposomal encapsulation.

Chemogenomics aims towards the systematic identification of small molecules that interact with the products of the genome and modulate their biological function. The establishment and expansion of a comprehensive ligand-target Structure-Activity Relationship matrix is following the elucidation of the human genome a key scientific challenge for the 21st century. Small chemical compounds are the first dimension of the ligand-target SAR matrix. Accordingly, the systematic expansion of the physically available and bioactive chemical space is a key objective of chemogenomics. The vital question is, how to enlarge the physically existing chemical space into the bioactive and drug-like spaces? Effective systematic expansion of the chemical space to reach a maximum of biological binding sites appears possible when conserved molecular recognition principles are the founding hypothesis for the design of the compounds. Such principles, including approaches focusing on target families, privileged scaffolds, protein secondary structure mimetics, co-factor mimetics, and DOS and BIOS libraries are summarized in this mini-review article.

Myocardial ischemia-reperfusion injury is a major cause of morbidity and mortality in developed countries. To date, the only treatment of complete ischemia is to restore blood flow; thus the search for new cardioprotective approaches is absolutely necessary to reduce the mortality associated with myocardial ischemia. Ischemia has long been considered to result in necrotic tissue damage but the reduction in oxygen supply can also lead to apoptosis. Therefore, in the last few years, mitochondria have become the subject of growing interest in myocardial ischemia- reperfusion since they are strongly involved in the regulation of the apoptotic process. Indeed, during ischemiareperfusion, pathological signals converge in the mitochondria to induce permeabilization of the mitochondrial membrane. Two classes of mechanisms, which are not mutually exclusive, emerged to explain mitochondrial membrane permeabilization. The first occurs via a non-specific channel known as the mitochondrial permeability transition pore (mPTP) in the inner and the outer membranes causing disruption of the impermeability of the inner membrane, and ultimately complete inhibition of mitochondrial function. The second mechanism, involving only the outer membrane, induces the release of cell death effectors. Thus, drugs able to block or to limit mitochondrial membrane permeabilization may be cytoprotective during ischemia-reperfusion. The objective of this review is to examine the pharmacological strategies capable of inhibiting mitochondrial membrane permeabilization induced by myocardial ischemia-reperfusion.

The shortcomings of native peptides as pharmaceuticals have been long known: short duration of action, lack of receptor selectivity, lack of oral bioavailability. However medicinal chemistry offers solutions to the first two limitations and oral bioavailability issues have been addressed with novel routes of administration (e.g. intranasal, inhalation) and injectable depot formulations. The principal issue for peptide drugs has been a short duration of action, widely assumed to be due to proteolysis. While proteolysis is a problem for native peptide structures, modification of the peptide structure by acylation, PEGylation, unnatural amino acids or restricted conformation can largely remove this issue. However rapid clearance from the blood into the urine remains an issue for even proteolytically stable molecules. Medicinal chemistry approaches here have been peptide modifications to slow release from the injection site (hydrophobic, hydrophilic, selfassociating depots), PEGylation, fatty acid acylation, and the like. Medicinal chemistry approaches used in successful peptide pharmaceuticals using unnatural amino acids to achieve depot formation are highlighted in this review.

Protein cysteines (cysteinyl residues) play critical roles in biological processes. In the course of protein evolution under oxidizing atmosphere of the Earth, organisms have utilized highly reactive cysteines in many proteins essential for maintenance of life, i.e. enzymes, transcriptional factors, cytoskeletons, and receptors. In some enzymes, sophistical cysteine modification characterizes each catalytic mechanism. In vivo modification of protein cysteines with natural chemical compounds modulates protein functions as a molecular switch. Oxidation/reduction, thiol-disulfide exchange, nitrosylation, sulfuration, thiolation, acylation and prenylation are involved. Some protein cysteines coordinate metals or metal cofactors such as a heme or an iron sulfur cluster to form metalloproteins, serving as sensor proteins, metalloenzymes or transcriptional factors. Information on the in vitro chemical modifications and their reaction specificities of protein cysteines are essential for the investigation of the mechanisms and functions of in vivo protein cysteine modifications. In this review, we also mention historically important knowledge other than recent results on protein cysteine modification and modulation of protein function to fertilize medical proteomics.

Our understanding of altered patterns of gene expression being responsible for many diseases has been growing thanks to modern molecular biological methods. Today, these changes can only be identified when tissue samples are available. Therefore, a noninvasive method allowing us to monitor gene expression in vivo would be valuable, not only as a research tool, but also for patient stratification before treatment and for treatment follow-up. Antisense oligonucleotides (ODN) have been considered to be suitable molecules to trace active genes in vivo, as well as to treat diseases by hybridising to its complementary messenger RNA (mRNA) sequence in the cells thereby preventing the synthesis of the peptide. However, the use of ODNs in the organisms are endangered by many hurdles such as physical barriers to pass and enzyme attack to be avoided. Positron emission tomography (PET) provides a most advanced in vivo imaging technology that allows the exploration of the fate of radionuclide-labelled antisense ODNs in the body; thereby providing information about biodistribution and quantitative accumulation in tissues to assess pharmacokinetic properties of ODNs. This kind of evaluation is important as part of the characterisation of antisense therapeutics but also as part of the development of antisense imaging agents. This review provides a general summary about the antisense concept and displays the present status of the antisense imaging field with the major achievements and remaining challenges on the long journey towards accomplishing in vivo monitoring of gene expression using PET.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid peptide that was initially isolated from hypothalamus extracts on the basis of its ability to stimulate the production of cAMP in cultured pituitary cells. Recent studies have shown that PACAP exerts potent neuroprotective effects not only in vitro but also in in vivo models of Parkinson's disease, Huntington's disease, traumatic brain injury and stroke. The protective effects of PACAP are based on its capacity to prevent neuronal apoptosis by acting directly on neurons or indirectly through the release of neuroprotective factors by astrocytes. These biological activities are mainly mediated through activation of the PAC1 receptor which is currently considered as a potential target for the treatment of neurodegenerative diseases. However, the use of native PACAP, the endogenous ligand of PAC1, as an efficient neuroprotective drug is actually limited by its rapid degradation. Moreover, injection of PACAP to human induces peripheral side effects which are mainly mediated through VPAC1 and VPAC2 receptors. Strategies to overcome these compromising conditions include the development of metabolically stable analogs of PACAP acting as selective agonists of the PAC1 receptor. This review presents an overview of the structure- activity relationships of PACAP and summarizes the molecular and conformational requirements for activation of PAC1 receptor. The applicability of PACAP analogs as therapeutic agents for treatment of neurodegenerative diseases is also discussed.

This review highlights the design and development of fesoterodine (Toviaz®) as a prodrug of 5-hydroxymethyl tolterodine (5-HMT), which is also the active metabolite of tolterodine, for the treatment of overactive bladder (OAB). Tolterodine and 5-HMT are both potent antimuscarinic agents. A prodrug approach was necessary for systemic bioavailability of 5-HMT after oral administration. Fesoterodine was selected amongst a series of ester analogues of 5-HMT to develop an advanced OAB treatment with an optimum biopharmaceutics profile, while maintaining a pharmacological link to tolterodine. While tolterodine and 5-HMT have similar antimuscarinic activity, the logD value, a determinant of lipophilicity and permeability across biological interfaces such as the gut wall and blood-brain barrier, is considerably lower for 5-HMT (0.74) versus tolterodine (1.83). In contrast to the cytochrome P450 (CYP) 2D6-mediated metabolism of tolterodine, 5- HMT formation from fesoterodine occurs via ubiquitous nonspecific esterases. Consequently, treatment with fesoterodine results in consistent, genotype-independent exposure to a singular active moiety (5-HMT); treatment with tolterodine results in CYP2D6 genotype-dependent exposure to varying proportions of two active moieties (5-HMT and tolterodine). At least partially due to the avoidance of variations in pharmacokinetic exposures observed with tolterodine, it was possible to develop fesoterodine with the flexibility of two efficacious and well-tolerated dosage regimens of 4 and 8 mg daily.