Naphthyl and coumarinyl biarylpiperazine derivatives as highly potent human beta-secretase inhibitors. Design, synthesis, and enzymatic BACE-1 and cell assays.

Twenty novel beta-secretase inhibitors containing biarylpiperazine moieties belonging to naphthyl and coumarinyl series were designed for their potential use in Alzheimer's disease therapy. Enzymatic and cell-based assays have been carried out. The biological results clearly demonstrate that specific substituents located at the N(4)-position of the piperazine ring result in excellent in vitro inhibitory potency (IC(50) values ranging between 40 and 70 nM). Variable temperature NMR and modeling studies are consistent with the obtained biological data, since these studies confirmed that introduction at the N(4)-position of the piperazine ring allows productive interactions within the BACE-1 active site, which appear to be determinative for high BACE-1 inhibitory activity. These results are of particular interest since some of the new analogues belonging to the naphthyl series are almost one log more active than the best inhibitor of the similar family recently reported.

1,1'-Xylyl bis-1,4,8,11-tetraaza cyclotetradecane: a new potential copper chelator agent for neuroprotection in Alzheimer's disease. Its comparative effects with clioquinol on rat brain copper distribution.

Dysfunction of copper metabolism leading to its excess or deficiency results in severe ailments. Recently, neurodegenerative disorders such as Alzheimer's disease have been associated with copper metabolism. Compounds having the ability to reduce copper levels in brain or to affect its distribution could have neuroprotective effects, mainly through a downregulation of the transcription of amyloid peptide precursor (APP). We report here the biological effect of compound 1,1'-xylyl bis-1,4,8,11-tetraaza cyclotetradecane, which specifically affects copper concentration in the brain cortex region. Its copper homeostatic activity is compared with that of clioquinol, a well-known drug, which has been recently reported as an active A beta-peptide clearance drug in vivo for Alzheimer's patients.

BACE-1 inhibitory activities of new substituted phenyl-piperazine coupled to various heterocycles: chromene, coumarin and quinoline.

The protease beta-secretase plays a central role in the synthesis of pathogenic amyloid-beta in Alzheimer's disease. Here, we report a new series of analogues based on the phenyl-piperazine scaffold coupled to various heterocyclic moieties, which demonstrate improved inhibitory activities on BACE-1 (FRET assay) compared to already known naphthyl counterparts. The obtained results suggest further structural modifications to access to more potent BACE-1 inhibitors.

Prospects for the resistance to HIV protease inhibitors: current drug design approaches and perspectives.

One of the major challenges raised by HIV chemotherapy is the insurgence of viral resistance to drugs. Resistance to antiviral therapy has been observed for each of the different classes of anti-viral drugs: nucleoside reverse-transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. The crucial question for AIDS drug research community is: Should we continue the search of new anti-HIV drugs which can overcome HIV resistance insurgence or should we consider resistance to anti-HIV drugs as a futile challenge? This review, focussed specifically on HIV antiprotease drugs, highlights the different strategies which have been developed to design new anti-protease drugs which could overcome HIV resistance, and also reviews the different classes of compounds (peptidomimetic or non-peptidomimetic) actually under investigation in order to face the problem of HIV resistance to drug.

Enhanced delivery of gamma-secretase inhibitor DAPT into the brain via an ascorbic acid mediated strategy.

Inhibition of gamma-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce pathogenic Abeta peptides, is an attractive approach for the treatment of Alzheimer's disease. We designed a gamma-secretase inhibitor bearing an ascorbic acid moiety which allows a specific delivery of the drug to the brain. Through, on the one hand, Abeta peptide production measurements by specific in vitro assays (gamma-secretase cell free assay and cell based assay on HEK 293 APP transfected cells) and on the other hand through pharmacokinetic studies on animal models, the new inhibitor shows a good pharmacokinetic profile as well as a potent gamma-secretase inhibitory activity in vitro. From the obtained results, it is expected that drug will be mainly delivered to the CNS with a low diffusion in the peripheral tissues. Consequently the side effects of this gamma-secretase inhibitor on the immune cells could be reduced.

Novel cyclized Pifithrin-alpha p53 inactivators: synthesis and biological studies.

Starting from various cyclic or bicyclic ketones, we have synthesized novel Pifithrin-alpha analogues bearing different methyl substituted phenyl ketone groups at the N3-position of the 2-iminothiazole heterocycle. From stability studies in a biological medium as well as under specific chemical conditions, we have shown by NMR techniques that through a dehydration process, some derivatives can generate their corresponding cyclized analogues. All of the new analogues, Pifithrin-like and polycyclic dehydrated derivatives were assessed for their p53 inactivation potency by measuring survival of cortical neurons, whose death was induced by the DNA-damaging agent etoposide. Pifithrin-alpha like 2f as well as the cyclic dehydrated 6b analogue were found to be one log more potent p53 inactivators than reference compound Pft-alpha, with EC50 values ranging around 30 nM. These results support the finding that p53 inactivation by Pft-alpha analogues could be also due to the presence of the cyclic dehydrated Pft-alpha forms, generated in situ in the biological assay incubation medium.

Substituted thiazolamide coupled to a redox delivery system: a new gamma-secretase inhibitor with enhanced pharmacokinetic profile.

Inhibition of gamma-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce pathogenic A beta peptides, is an attractive approach for the treatment of Alzheimer's disease. We have designed a new gamma-secretase thiazolamide inhibitor bearing a dihydronicotinoyl moiety as Redox Delivery System which allows specific delivery of the drug to the brain. Through, on the one hand, A beta peptide production measurements by specific in vitro assays (gamma-secretase Cell Free assay and Cell Based assay on HEK 293 APP transfected cells) and, on the other hand, pharmacokinetic studies on animal models, the new inhibitor shows a good pharmacokinetic profile as well as a potent gamma-secretase inhibitory activity in vitro. From the obtained results, it is expected that drug will be mainly delivered to the CNS with low diffusion in the peripheral tissues. Consequently the side effects of this gamma-secretase inhibitor on the immune cells could be reduced.

New 2-bromomethyl-8-substituted-benzo[c]chromen-6-ones. Synthesis and biological properties.

New 2-bromomethyl-8-substituted-benzo[c]chromen-6-ones have been synthesized and their bioactive properties have been evaluated on different enzymatic models: serine proteases (trypsin and alpha-chymotrypsin), HIV aspartyl protease, nitric oxide synthase and a panel of protein kinases. These new derivatives can provide upon chemical or enzymatic attack, very reactive quinonimine methide intermediates, which could be utilized for the design of enzyme inhibitors. We found that some of these new derivatives exhibit modest inhibitory activities on the studied enzyme models, but it could be improved after structure optimization.

N-acyl substituted 7-amino-4-chloroisocoumarin: a peptide degradation model via an imide mechanism.

During the coupling reaction between 3-alkoxy-7-amino-4-chloroisocoumarin and N-acyl alanine dipeptide, an unexpected deamidation reaction was observed. The proposed mechanism for this reaction involved the formation of an imide intermediate which after cleavage led to the release of amino acid moiety. The described deamidation reaction represents the first chemical model involving a non-peptidic moiety, which mimics biological and chemical deamidation processes occurring in proteins or peptides incorporating an asparagine or a glutamine residue.

New antiviral nucleoside prodrugs await application.

In this review, we intend to highlight outstanding concepts of antiviral nucleoside prodrugs which have been developed in recent years, so as to improve the efficacy of a given antiviral drug or to overcome some drug deficiencies. Examples of antiviral carrier-linked nucleoside prodrugs or nucleoside bioprecursors are described, and their active mechanisms discussed. The described nucleoside prodrugs are classified in two structural classes: prodrugs bearing molecular modifications on the sugar moiety and prodrugs bearing molecular modifications on the nucleic base. Despite the important research work accomplished through out the world during the last few years in developing improved antiviral drugs for the treatment of HIV (human immunodeficiency virus), HBV (hepatitis B virus), HCV (hepatitis C virus), HSV (herpes simplex virus), HCMV (human cytomegalovirus), etc infections, only few nucleoside antiviral prodrugs are marketed, while promising prodrugs deriving from original concepts were developed. The most relevant concepts are discussed: (1) - pronucleotide approach allows the design of prodrugs, which by-pass the first kinase phosphorylation step; (2) - drug design based on Bodor's concept for brain delivery improved drugs and (3) - 5'-O-carbonate nucleosides and deaminase approaches, which allow active drug regeneration. Nonetheless, none of these innovative models have reached the market.