Current Pharmaceutical Design - Volume 11, Issue 26, 2005

Alzheimer's Disease (AD) and its associated morbidity continues to be a devastating condition for patients afflicted with this ailment, as well as the family and caregivers of patients. Although great strides have been made with respect to understanding the etiology associated with AD, it still remains a large unmet medical need, affecting nearly one in ten individuals over the age of 65, and nearly one in two persons by age 85 [1]. This issue of Current Pharmaceutical Design addresses AD, dementia and cognitive decline. In organizing this edition, we have sought out experts in the pharmaceutical industry who are actively pursuing approaches to treat these afflictions. As a treatment for cognitive decline, Rose and coworkers [1] discuss inhibition of phosphodiesterases (PDEs). A rationale is presented for the inhibition of PDEs as a second messenger system to inhibit cyclic adenosine monophosphate (cAMP). cAMP plays a key role in biochemical processes that regulate the process of memory consolidation. The pathophysiology of AD and the immune response is discussed by Nelson [2]. Transgenic animals are being developed which explore this relationship. The relative merits of transgenic animals, immunotherapy, and their relevance to simplifying clinical trials are detailed. Clader and Wang [3] approach the treatment of the loss of cognitive function associated with AD by studying the loss of cholinergic activity. In an effort to increase cholinergic function, regulation of the muscarinic receptors has been studied. Stimulation of the muscarinic M1 receptor by M1 agonists improves cognitive function. In contrast, antagonism of the M2 receptor improves cognitive function. The relative structure activity relationships of agonists and antagonists of the receptors are presented. The paper of Churcher and Beher [4] provide an account of the current approaches to treat AD by decreasing amyloid β (Aβ)-associated toxicity by inhibiting gamma secretase, an enzyme responsible for the final step in Aβ synthesis. The structure activity relationship of inhibitors is discussed, as well as the potential pitfalls associated with this approach. Inhibitors of gamma secretase have also been shown to inhibit Notch processing, resulting in peripheral toxicity. Differentiating between these two processes may prove to be a difficult task. Thompson, Bronson and Zusi [5] present a promising alternative to the inhibition of gamma secretase for decreasing central Aβ levels, by inhibition of β-secretase (BACE) in AD patients. The rationale for BACE inhibition is presented, as well as detailed structure activity relationships. We would like to thank all of the authors for their commitment in writing these reviews. Their work will contribute to a greater understanding of AD and will hopefully speed the discovery and development of treatments for this important therapeutic target. References [1] Rose GM, Hopper A, De Vivo M, Tehim A. Phosphodiesterase Inhibitors for Cognitive Enhancement. Curr Pharm Design 2005; 11(26): 3329-3334. [2] Nelson RB. The Dualistic Nature of Immune Modulation in Alzheimer's Disease: Lessons from the Transgenic Animals. Curr Pharm Design 2005; 11(26): 3335-3352. [3] Clader JW, Wang Y. Muscarinic Receptor Agonists and Antagonists in the Treatment of Alzheimer's Disease. Curr Pharm Design 2005; 11(26): 3353-3361. [4] Churcher I, Beher D. g-Secretase as a Therapeutic Target for the Treatment of Alzheimer's Disease. Curr Pharm Design 2005; 11(26): 3363-3382. [5] Thompson LA, Bronson JJ, Zusi FC. Progress in the Discovery of BACE Inhibitors. Curr Pharm Design 2005; 11(26): 3383-3404.

An effective treatment for age-related cognitive deficits remains an unmet medical need. Currently available drugs for the symptomatic treatment of Alzheimer's disease or other dementias have limited efficacy. This may be due to their action at only one of the many neurotransmitter systems involved in the complex mechanisms that underlie cognition. An alternative approach would be to target second messenger systems that are utilized by multiple neurotransmitters. Cyclic adenosine monophosphate (cAMP) is a second messenger that plays a key role in biochemical processes that regulate the cognitive process of memory consolidation. Prolongation of cAMP signals can be accomplished by inhibiting phosphodiesterases (PDEs). Eleven PDE families, comprised of more than 50 distinct members, are currently known. This review summarizes the evidence demonstrating that rolipram, a selective inhibitor of cAMP-selective PDE4 enzymes, has positive effects on learning and memory in animal models. These data provide support for the general approach of second messenger modulation as a potential therapy for cognitive dysfunction, and specifically suggest that PDE4 inhibitors may have utility for improving the symptoms of cognitive decline associated with neurodegenerative and psychiatric diseases.

There is extensive evidence that changes in immune system activation accompany the pathological changes of Alzheimer's disease (AD), but a mechanistic understanding of how the immune system actually participates in disease pathogenesis is still largely lacking. Because of the complexity of the immunological response, and the difficulty in identifying the key molecular players that underlie any given immunological response, expanding our understanding of the immunological response in AD beyond its descriptive stages has not been a straightforward exercise. The development of transgenic animals that form deposits of Aβ peptide in their brains has provided an unexpected dividend to those interested in the immunological response characterizing AD. Several of these transgenic models develop structures greatly resembling neuritic plaques, a hallmark feature of AD brain that is also a focal point of the immunological response occurring in AD. Genetic and pharmacological manipulation of these Aβ-depositing transgenic mice is providing some intriguing and unexpected insights into the role of innate and adaptive immune mechanisms in the pathogenesis of AD. This review will discuss immunological perspectives that have arisen from research using Aβ-depositing transgenic mice, and place these perspectives in the context of epidemiological and genetic studies that have previously suggested a role for the immune system in AD. The emerging story affirms the likely role of innate and adaptive immune mechanisms in the pathogenesis of AD, but provides a cautionary note as to the difficulties that are likely to face potential immunomodulatory therapies due to the dualistic beneficial and detrimental roles that immune mechanisms appear to play in AD.

One of the consistent findings in the brains of Alzheimer's Disease (AD) patients is loss of cholinergic function. The cholinergic approach to treatment of AD involves counteracting this loss in cholinergic activity by pharmacological intervention to increase cholinergic transmission. The cognitive effects of acetylcholine are mediated via the muscarinic M1 receptor. Direct stimulation of this receptor using muscarinic M1 agonists improves cognition in animal models and improves performance in cognitive tests in Alzheimer's patients. Alternatively, antagonists of central presynaptic M2 receptors improves cognition by increasing the central release of acetylcholine. Both approaches require high selectivity for one muscarinic receptor sub-type both for efficacy and to avoid cholinergic side effects. In this review summarizes recent progress in the identification and characterization of selective muscarinic receptor ligands for the treatment of Alzheimer's disease.

An effective, disease-modifying treatment of Alzheimer's disease (AD) remains one of the most significant unmet needs in modern medicine. As a result of the extensive research in the area, the mechanisms underlying the disease are now much better understood than at any time before. A significant amount of evidence points to the central role of β-amyloid (Aβ) peptide-mediated toxicity in the disease etiology and strategies to remove this species from the central nervous system (CNS) have been actively pursued. The enzyme responsible for the final step in Aβ synthesis, γ-secretase, has emerged as an attractive drug target and intensive research has transformed this enzyme from shadowy beginnings into a well characterised member of a new family of intramembrane-cleaving aspartyl proteases. Many inhibitors across diverse structural classes have been discovered and have demonstrated a lowering of central Aβ levels in preclinical models of AD. It has also become increasingly evident more recently that γ-secretase also mediates a range of cleavages of alternative transmembrane peptides most notably the Notch receptor and the functional consequences of this activity have attracted much attention. The ultimate therapeutic benefit of γ-secretase inhibitors and the effect of alternative, mechanism-based activities can only be judged when clinical data is forthcoming. In this review we describe the literature regarding the discovery of the nature of γ-secretase, the development of small molecule inhibitors and their in vivo profiles.

Dementia caused by Alzheimer's disease is a large medical burden on society in the developed world. Current treatments are largely symptomatic, and there is an urgent need for therapies which can interrupt or reverse the progression of disease. A number of strategies for intervention are being actively pursued; among the most promising is the inhibition of β-secretase, or BACE. BACE is the enzyme responsible for N-terminal cleavage of the Alzheimer's precursor protein leading to the production of the beta-amyloid peptide. This cascade ultimately leads to the formation of amyloid plaques, one of the hallmark lesions of the disease. It is expected that inhibitors of BACE may therefore serve as an effective disease-modifing therapy for the treatment of AD. This concept has received significant attention by both academics and the pharmaceutical industry. This review focuses on a discussion of the reported structure-activity relationships for inhibitors of this important therapeutic target.

RNAi (RNA interference) was originally detected in Caenorhabditis elegans as biological response to exogenous double-stranded RNA (dsRNA), which induces very effective sequence-specific silencing of gene expression. Further investigations revealed that RNAi can occur in many eukaryotic species. Increasing understanding of the biochemical components of RNAi indicates the existence of a conserved machinery for dsRNA-induced gene silencing that acts in two steps. In the first step, an RNase III family nuclease called Dicer processes the dsRNA to small interfering RNAs (siRNAs) 21-23 nt in length. These siRNAs enter a multimeric nuclease complex that identifies target mRNAs through their homology to siRNAs and induce destruction of the corresponding mRNAs. Since RNAi has become an excellent strategy for gene silencing, it is tempting to apply this technology to 'knock-down' gene expression in living animals. The generation of transgenic mice from embryonic stem cells expressing small hairpin RNAs (shRNAs) has provided evidence for in vivo application of RNAi. Furthermore, different experimental strategies have been developed to analyze the influence of chemically synthesized siRNAs and of vector-based shRNAs on the expression of different transgenes and endogenous genes in vivo. Recent studies describe the in vivo delivery of siRNAs to inhibit transgene expression in certain organs of adult mice, predominately murine liver. Strategies for the inhibition of cellular proliferation by systemic treatment of tumor-bearing animals with siRNAs are beginning to emerge. They are of utmost interest for systemic diseases such as cancer. In addition, several groups have shown that RNAi can also be used to block the infectivity or suppress the replication of different RNA viruses relevant to human diseases including human immunodeficiency virus-1 (HIV-1) and hepatitis C virus (HCV). In summary, multiple lines of evidence indicate that RNAi seems to become a powerful tool for the fight against undesirable gene expression in human diseases.

The endocannabinoid system has been involved in the control of several neurophysiological and behavioural responses. Indeed, recent studies have suggested that the cannabinoid system could represent an important substrate for the control of emotional behaviour, and further research would probably help to identify new promising therapeutic targets. This paper reviews the results obtained in different animal models used to investigate emotional states after the manipulation of the endocannabinoid system. Cannabinoid compounds can induce anxiogenic- and anxiolytic-like responses in rodents depending on the experimental conditions. Studies using knockout mice lacking the CB1 cannabinoid receptors have shown the participation of this receptor in several behavioural responses including anxiety- and depressive-like states. Furthermore, the endocannabinoid system regulates the hypothalamic-pituitary adrenal axis, which is involved in providing an appropriate response to stressful situations. Recent studies have also demonstrated that the endocannabinoids can function as retrograde messengers, modulating the release of different neurotransmitter, including opioids, GABA and cholecystokinin that have been classically involved in the control of anxiety-like responses. All this recent information has further clarified the role played by the endogenous cannabinoid system in the control of emotional behaviour and provides data to support a new possible therapeutic use of cannabinoid compounds.

Eicosanoids are potent biologically active arachidonic acid-derived lipid mediators that are intimately involved in inflammation and cancer. Cyclooxygenase (COX), the key enzyme in prostaglandin (PG) biosynthesis, controls one of the major pathways of arachidonic acid metabolism and is the main target for non-steroidal anti-inflammatory drugs (NSAIDs). COX exists in two distinct isoforms, COX-1 and COX-2, the latter being primarily involved in inflammation and cell proliferation. For this reason, in recent years, selective COX-2 inhibitors, that achieve the same anti-inflammatory efficacy as traditional NSAIDs but minimize the risk of unwanted side-effects, have been developed. On the other hand, emerging information has appreciated the role of other arachidonic acid metabolic pathway (the 5-lipoxygenase (5-LO) pathway) in producing and maintaining inflammation. Moreover, it is now being perceived that COX-2 and 5-LO have converging functions not only in inflammation but also in cell proliferation and neo-angiogenesis. In this regard, there is evidence that COX-2 and 5-LO are co-expressed and up-regulated in a number of inflammatory and neoplastic disorders, and that COX-2 as well as 5-LO inhibitors have beneficial effects in inflammatory diseases and are being investigated as potential anticancer drugs. This review provides an overview and an update of the progress achieved in the knowledge of COX-2 and 5-LO pathways and their involvement in inflammation and cancer. It also proposes a model of integrated pharmacological intervention on these pathways and reviews the information available regarding the use of the novel dual COX-2/5-LO inhibitors that block both pathways equally well.

Acute myelogenous leukemia (AML) is a difficult disease to treat, and better treatments are needed. Molecular targeted therapy represents a novel therapeutic approach. The FLT3 tyrosine kinase receptor is mutated in approximately one-fourth to one-third of patients with AML. Normally, binding of FLT3 ligand to the FLT3 receptor leads to phosphorylation of tyrosine residues and activation of the receptor. This in turn leads to induction of intracellular signaling pathways essential to regulation of cell proliferation and apoptosis. Two classes of FLT3 activating mutations have been identified in AML patients: internal tandem duplications (ITDS) and point mutations in the activating loop of the kinase domain. Both mutations result in constitutive FLT3 tyrosine kinase activity and lead to transformation of hematopoietic cell lines in vivo and in vitro. FLT3 ITDs are also an independent poor prognostic factor for overall survival and disease free survival in patients with AML. Therefore, targeting FLT3 mutations represents a potential therapeutic target for AML. This review will discuss the biology and clinical significance of FLT3 and FLT3 mutations in cell growth and signaling. In addition, I will discuss some of the novel FLT3 inhibitors which are entering clinical trials for AML.