Мероприятия по предупреждению травматизма на ООО "Газпром Трансгаз Томск"

A series of macrocyclic peptidic BACE-1 inhibitors was designed. While potency on BACE-1 was rather high, the first set of compounds showed poor brain permeation and high efflux in the MDCK-MDR1 assay. The replacement of the secondary benzylamino group with a phenylcyclopropylamino group maintained potency on BACE-1, while p-glycoprotein-mediated efflux was significantly reduced and brain permeation improved. Several compounds from this series demonstrated acute reduction of Abeta in human APP-wildtype transgenic (APP51) mice after oral administration

A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-β and neuroinflammation in APP transgenic mice

BACKGROUND: Alzheimer’s disease (AD) is the most common form of dementia, the number of affected individuals is rising, with significant impacts for healthcare systems. Current symptomatic treatments delay, but do not halt, disease progression. Genetic evidence points to aggregation and deposition of amyloid-β (Aβ) in the brain being causal for the neurodegeneration and dementia typical of AD. Approaches to target Aβ via inhibition of γ-secretase or passive antibody therapy have not yet resulted in substantial clinical benefits. Inhibition of BACE1 (β-secretase) has proven a challenging concept, but recent BACE1inhibitors can enter the brain sufficiently well to lower Aβ. However, failures with the first clinical BACE1 inhibitors have highlighted the need to generate compounds with appropriate efficacy and safety profiles, since long treatment periods are expected to be necessary in humans. RESULTS: Treatment with NB-360, a potent and brain penetrable BACE-1 inhibitor can completely block the progression of Aβ deposition in the brains of APP transgenic mice, a model for amyloid pathology. We furthermore show that almost complete reduction of Aβ was achieved also in rats and in dogs, suggesting that these findings are translational across species and can be extrapolated to humans. Amyloid pathology may be an initial step in a complex pathological cascade; therefore we investigated the effect of BACE-1 inhibition on neuroinflammation, a prominent downstream feature of the disease. NB-360 stopped accumulation of activated inflammatory cells in the brains of APP transgenic mice. Upon chronic treatment of APP transgenic mice, patches of grey hairs appeared. CONCLUSIONS: In a rapidly developing field, the data on NB-360 broaden the chemical space and expand knowledge on the properties that are needed to make a BACE-1 inhibitor potent and safe enough for long-term use in patients. Due to its excellent brain penetration, reasonable oral doses of NB-360 were sufficient to completely block amyloid-β deposition in an APP transgenic mouse model. Data across species suggest similar treatment effects can possibly be achieved in humans. The reduced neuroinflammation upon amyloid reduction by NB-360 treatment supports the notion that targeting amyloid-β pathology can have beneficial downstream effects on the progression of Alzheimer’s disease

The BACE inhibitor NB-360 in preclinical models: From β-amyloid reduction to downstream disease-relevant effects

Inhibition of Beta-site- APP Cleaving Enzyme-1 (BACE-1) is a current approach to fight the β-amyloid (Aβ) deposition in the brains of patients with Alzheimer’s disease, and a number of BACE-1 inhibitors are currently being tested in clinical trials. The BACE-1 inhibitor NB-360, although not a clinical compound, turned out as a valuable pharmacological tool to investigate the effects of BACE-1 inhibition on the deposition of different Aβ species in APP transgenic mice. Furthermore, chronic animal studies with NB-360 discovered relationships between BACE-1 inhibition, Aβ deposition, and Aβ-related downstream effects on neuroinflammation, neuronal function and markers of neurodegeneration. NB-360 effects on the processing of physiological BACE-1 substrates as well as on non-enzymatic BACE-1 functions have been investigated and complement studies performed with BACE-1 knock-out mice. Since NB-360 is also an inhibitor for BACE-2, non-clinical studies revealed physiological effects of BACE-2 inhibition

Discovery of Cyclic Sulfone Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure Based Design and In Vivo Reduction of Amyloid β-Peptides

Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the SAR development was supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed to enhance potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with CNS drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure based optimization we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC50 of 2 and 50 nM, respectively and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 µmol/kg demonstrated significant reduction of brain Aβ levels

Prediction of PV Power Production with Neural ODEs on the base of Weather data

Predicting energy production from photovoltaics (PV) is crucial for efficient energy management. In order to apply different operating strategies, it is necessary to predict the expected amounts of PV energy. The operating strategies are typically optimized with regard to economic or technical goals or a combination of both. Within this work, we show a possibility to predict PV power production using local weather data and Neural Ordinary Differential Equations (NODE). Based on the measured values from the PV system and an associated weather station, the NODE is trained and validated with regard to PV production. The measurement data are collected from the PV system of the former Campus North of Offenburg University of Applied Sciences

Structure-based design and synthesis of macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors.

The hydroxyethylene octapeptide inhibitor OM99-2 served as starting point to create the tripeptide inhibitor 1 and its analogues 2a and b. An X-ray co-crystal structure of 1 with BACE-1 allowed the design and syntheses of a series of macrocyclic analogues 3a-h covalently linking the P1 and P3 side-chains. These inhibitors show improved enzymatic potency over their open-chain analogue. Inhibitor 3h also shows activity in a cellular system

Discovery of Cyclic Sulfoxide Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure Based Design and in Vivo Reduction of Amyloid β-Peptides

Previous structure based optimization in our laboratory led to the identification of a novel, high-affinity cyclic sulfone hydroxyethylamine-derived inhibitor such as 1 that lowers CNS-derived Aβ following oral administration to transgenic APP51/16 mice. Herein we report SAR development in the S3 and S2’ subsites of BACE1 for cyclic sulfoxide hydroxyethyl¬amine inhibitors, the synthetic approaches employed in this effort, and in vivo data for optimized compounds such as 11d