A Synthesis of Levetiracetam based on (S)-N-Phenylpantolactam as chiral auxiliary

Risoluzione di composti di interesse farmaceutic

HUPRINETACRINE HYBRIDS AS A NOVEL FAMILY OF MULTI-TARGET DRUG CANDIDATES AGAINST ALZHEIMER\u2019S AND PRION DISEASES

Several years ago, a short series of racemic huprine-tacrine hybrids was developed as a new class of dual binding site acetylcholinesterase (AChE) inhibitors. These compounds consisted of: i) a unit of huprine Y, a compound with one of the highest affinities for the active site of AChE yet reported, ii) a unit of tacrine, a compound with known affinity for the peripheral site of AChE, and iii) a linker of appropriate length to allow simultaneous binding to both the active and peripheral sites of the enzyme. Recently, the series of huprine-tacrine hybrids has been extended with the synthesis of shorter and longer homologues. Also, the two enantiomers of two of the most potent racemic huprine-tacrine hybrids have been independently synthesized from readily available (-)- and (+)-huprine Y, and their binding mode has been studied by molecular dynamics simulations. Moreover, additional pharmacological and pharmacokinetic studies have been undertaken. Among other properties, some huprine-tacrine hybrids have been shown to be able to significantly inhibit the AChE-induced A-beta and prion peptide aggregation, two key pathogenic processes involved in AD and in prion diseases, and seem to be able to cross the blood-brain barrier

SYNTHESIS, PHARMACOLOGICAL EVALUATION, AND MOLECULAR MODELING OF A NOVEL FAMILY OF 6-CHLOROTACRINE-BASED DUAL BINDING SITE ACETYLCHOLINESTERASE INHIBITORS

In the last decade, the design of novel classes of inhibitors of the enzyme acetylcholinesterase (AChE) as therapeutic interventions for Alzheimer\u2019s disease (AD) has been mostly driven by the pivotal finding that AChE can bind the β-amyloid peptide (Aβ), thereby promoting Aβ aggregation as an early event in the neurodegenerative cascade of AD. Blockade of the peripheral site of AChE, the Aβ recognition zone within the enzyme, is expected to affect the AChE-induced Aβ aggregation and could be a potential strategy to modulate the progression of AD. Novel classes of AChE inhibitors (AChEIs) targeting the peripheral site of AChE are emerging as promising disease-modifying anti-Alzheimer drug candidates. Of particular interest are the so-called dual binding site AChEIs, i.e. inhibitors able to simultaneously bind both the active and peripheral sites of AChE, which exhibit significant Aβ antiaggregating effects and high AChE inhibitory potencies. Two isomeric series of dual binding site AChEIs have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and self-induced Aβ aggregation and β-secretase (BACE-1). The new hybrids consist of a unit of 6-chlorotacrine and a multicomponent reactionderived pyrano[3,2-c]quinoline scaffold as the active-site and peripheral-site interacting moieties, respectively, connected through an oligomethylene linker containing an amido group at variable position. Molecular modeling studies have confirmed the dual site binding of these hybrids, which retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine, while exhibiting a significant in vitro Aβ anti-aggregating effect and BACE-1 inhibitory activity, thus constituting promising anti-Alzheimerdrug candidates

NOVEL DONEPEZIL-BASED INHIBITORS OF CHOLINESTERASES AND ACETYLCHOLINESTERASE-INDUCED BETA-AMYLOID AGGREGATION

A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced beta-amyloid (A-beta) aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position than tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether which connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant A-beta antiaggregating activity, which makes them promising anti-Alzheimer drug candidates

SYNTHESIS, PHARMACOLOGICAL EVALUATION, AND MOLECULAR MODELING OF A NOVEL FAMILY OF 6-CHLOROTACRINE-BASED DUAL BINDING SITE ACETYLCHOLINESTERASE INHIBITORS

Two isomeric series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and self-induced beta-amyloid (A-beta) aggregation and gamma-secretase (BACE-1). The new hybrids consist of a unit of 6-chlorotacrine and a multicomponent reaction-derived pyrano[3,2-c]quinoline scaffold as the active-site and peripheral-site interacting moieties, respectively, connected through an oligomethylene linker containing an amido group at variable position. Molecular modeling studies have confirmed the dual site binding of these hybrids, which retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine, while exhibiting a significant in vitro A-beta anti-aggregating effect and BACE-1 inhibitory activity, thus constituting promising anti-Alzheimer drug candidates

Effects of age on the risk of dying from pulmonary embolism or bleeding during treatment of deep vein thrombosis

BACKGROUND: The risk of patients dying of pulmonary embolism (PE) or bleeding during the treatment of deep vein thrombosis (DVT), and whether these risks are influenced by patient age, has not been thoroughly studied. METHODS: We used data from the Registro Informatizado de la Enfermedad TromboEmb\uf3lica (RIETE) to assess the risk of fatal PE and fatal bleeding in 16,199 patients with lower limb DVT (without symptomatic PE at the time of inclusion) during the 3 months after diagnosis, with patients categorized according to age. RESULTS: During the 3 months of anticoagulant treatment, there were 31 fatal PEs (0.19%) and 83 fatal hemorrhages (0.51%). During the first 7 days of therapy, the frequency of fatal PEs was similar to that of fatal bleeding (12 vs 14 deaths, respectively; odds ratio [OR], 0.86; 95% confidence interval [CI], 0.39-1.87). However, from days 8 to 90, the frequency of fatal bleeding was greater than that of fatal PE (69 vs 19 deaths; OR, 3.64; 95% CI, 2.22-6.20). The higher frequency of fatal bleeding compared with fatal PE from days 8 to 90 appeared to be confined to patients who were aged 65 60 years. Multivariate analysis showed that patient age was independently associated with an increased risk of death from bleeding during the first 3 months: every 10 years the OR increased by 1.37 (95% CI, 1.12-1.67). CONCLUSIONS: During the first week of treatment, the risk of fatal bleeding and fatal PE were similar. Then, particularly in patients who were aged 65 60 years, the risk of dying from bleeding exceeded the risk of dying from PE

Outcomes in Neurosurgical Patients Who Develop Venous Thromboembolism: A Review of the RIETE Registry

OBJECTIVES: Registro Informatizado de Enfermedad TromboEmb\uf3lica (RIETE) database was used to investigate whether neurosurgical patients with venous thromboembolism (VTE) were more likely to die of bleeding or VTE and the influence of anticoagulation on these outcomes. METHODS: Clinical characteristics, treatment details, and 3-month outcomes were assessed in those who developed VTE after neurosurgery. RESULTS: Of 40 663 patients enrolled, 392 (0.96%) had VTE in less than 60 days after neurosurgery. Most patients in the cohort (89%) received initial therapy with low-molecular-weight heparin, (33% received subtherapeutic doses). In the first week, 10 (2.6%) patients died (8 with pulmonary embolism [PE], no bleeding deaths; P = .005). After the first week, 20 (5.1%) patients died (2 with fatal bleeding, none from PE). Overall, this cohort was more likely to develop a fatal PE than a fatal bleed (8 vs 2 deaths, P = .058). CONCLUSIONS: Neurosurgical patients developing VTE were more likely to die from PE than from bleeding in the first week, despite anticoagulation

D-dimer levels and 90-day outcome in patients with acute pulmonary embolism with or without cancer

BACKGROUND: The prognostic value of D-dimer testing in patients with acute pulmonary embolism (PE) has not been thoroughly studied. METHODS: We used the RIETE Registry data to assess the 90-day prognostic value of increased IL Test D-dimer levels at baseline in patients with PE, according to the presence or absence of cancer. RESULTS: As of May 2013, 3,283 patients with acute PE underwent D-dimer testing using IL Test D-dimer. Among 2,588 patients without cancer, those with D-dimer levels in the highest quartile had a higher rate of fatal PE (2.6% vs. 0.9%; p=0.002), fatal bleeding (1.1% vs. 0.3%; p=0.017) and all-cause death (9.1% vs. 4.4%; p<0.001) at 90 days compared with those with levels in the lowest quartiles. Among 695 patients with cancer, those with levels in the highest quartile had a similar rate of fatal PE or fatal bleeding but higher mortality (35% vs. 24%; p<0.01). On multivariate analysis, non-cancer patients with D-dimer levels in the highest quartile had an increased risk for fatal PE (odds ratio [OR]: 3.3; 95% CI: 1.6-6.6), fatal bleeding (OR: 4.3; 95% CI: 1.4-13.7) and all-cause death (OR: 2.1; 95% CI: 1.4-3.1) compared with patients with levels in the lowest quartiles. CONCLUSIONS: Non-cancer patients with acute PE and IL Test D-dimer levels in the highest quartile had an independently higher risk for fatal PE, fatal bleeding and all-cause death at 90 days than those with levels in the lowest quartiles. In patients with cancer, D-dimer levels failed to predict fatal PE or fatal bleeding

Clinical presentation and outcome of venous thromboembolism in COPD

Chronic obstructive pulmonary disease (COPD) is a moderate risk factor for venous thromboembolism (VTE), but neither the clinical presentation nor the outcome of VTE in COPD patients is well known. The clinical presentation of VTE, namely pulmonary embolism (PE) or deep venous thrombosis (DVT), and the outcome at 3 months (death, recurrent VTE or bleeding) were compared between 2,984 COPD patients and 25,936 non-COPD patients included in the RIETE (Registro Informatizado de la Enfermedad TromboEmb\uf3lica) registry. This ongoing international, multi-centre registry includes patients with proven symptomatic PE or DVT. PE was the more frequent VTE presentation in COPD patients (n = 1,761, 59%). PE presentation was more significantly associated with COPD patients than non-COPD patients (OR 1.64, 95% CI 1.49-1.80). During the 3-month follow-up, mortality (10.8% versus 7.6%), minor bleeding (4.5% versus 2.3%) or first VTE recurrences as PE (1.5% versus 1.1%) were significantly higher in COPD patients than in non-COPD patients. PE was the most common cause of death. COPD patients presented more frequently with PE than DVT. It may explain the worse prognosis of COPD patients, with a higher risk of death, bleeding or VTE recurrences as PE compared with non-COPD patients. Further therapeutic options are needed

Silent pulmonary embolism in patients with proximal deep vein thrombosis in the lower limbs

BACKGROUND: One in every three patients with deep vein thrombosis (DVT) in the lower limbs may have silent pulmonary embolism (PE), but its clinical relevance has not been thoroughly studied. METHODS: We used the RIETE Registry data to study patients with proximal DVT and no PE symptoms, but with a systematic search for PE. We compared the outcome of DVT patients with silent PE and those with no PE. RESULTS: Of 2375 patients with DVT, 842 (35%) had silent PE and 1533 had no PE. During the first 15 days of anticoagulation, patients presenting with silent PE had a higher incidence of symptomatic PE events than those with no PE (0.95% vs. 0.13%; P = 0.015), with a similar incidence of major bleeding (0.95% vs. 1.63%; P = 0.09). In patients with silent PE, the incidence of PE events during the first 15 days was equal to the incidence of major bleeding (eight events each), but in those with no PE the incidence of PE events was eight times lower (3 vs. 25 bleeding events). Multivariate analysis confirmed that DVT patients with silent PE had a higher incidence of symptomatic PE events during the first 15 days than those with no PE (odds ratio, 4.80; 95% CI, 1.27-18.1), with no differences in bleeding. CONCLUSIONS: DVT patients with silent PE at baseline had an increased incidence of symptomatic PE events during the first 15 days of anticoagulant therapy. This effect disappeared after 3 months of anticoagulation