(Trimethylsilyl)alanine: a Metabolically Stable 'Bio-Isostere' for Phenylalanine

The preparation of protected derivatives of enantiomerically pure β-(trimethylsilyl)alanine (1) and their chemical properties are decribed. Examples of renin inhibitory peptides, containing 1 are given, which demonstrates its use as a 'bio-isosteric' replacement for phenylalanine (2)

Renin-Inhibitoren – Von 'transition-state' Analogen und Peptidmimetika zu blutdrucksenkenden Wirkstoffen

During the last 10 years, a great worldwide effort was devoted towards the discovery of orally active renin inhibitors as blood-pressure-lowering drugs. Design principles and synthesis of successive generations of renin inhibitors are discussed using selected examples. The progression from the concept of the 'transition-state' inhibitor, through compounds stable towards protease cleavage and hence towards orally active 'non-peptide' inhibitors is described. All this experience in design, molecular modelling, and synthesis – although not too successful for renin itself – has been applied to the search for inhibitors of other proteolytic enzymes. Thus, the extremely rapid progress made in identifying HIV-protease inhibitors was possible largely through the 'know how' obtained during the search for renin inhibitors

Diastolic dysfunction precedes myocardial hypertrophy in the development of hypertension

Background: Left ventricular (LV) hypertrophy and impaired diastolic function may occur early in systemic hypertension, but longitudinal studies are missing. Methods: We performed an echocardiographic follow-up study in young initially normotensive male offspring of hypertensive (OHyp) (n = 25) and normotensive (ONorm) (n = 17) parents. Blood pressure (BP), LV mass, and mitral inflow were determined at baseline and after 5 years. Pulmonary vein flow pattern assessment and septal myocardial Doppler imaging were additionally performed at follow-up. Results: At follow-up, BP was not significantly different between the two groups (128 ± 11 / 84 ± 10 v 123 ± 11 / 81 ± 5 mm Hg, OHyp v ONorm) but five OHyp had developed mild hypertension. LV mass index remained unchanged and was not different between the two groups at follow-up (92 ± 17 v 92 ± 14 g/m2). Diastolic echocardiographic properties were similar at baseline, but, at follow-up, the following differences were found: mitral E deceleration time (209 ± 32 v 185 ± 36 msec, P < .05) and pulmonary vein reverse A wave duration (121 ± 15 v 107 ± 12 msec, P < .05) were prolonged in the OHyp as compared to the ONorm. Compared to the normotensive subjects, the five OHyp who developed hypertension had more pronounced alterations of LV diastolic function, that is, significantly higher mitral A (54 ± 7 v 44 ± 9 cm/sec, hypertensives v normotensives, P < .05), lower E/A ratio (1.31 ± 0.14 v 1.82 ± 0.48, P < .05), increased systolic-to-diastolic pulmonary vein flow ratio (1.11 ± 0.3 v 0.81 ± 0.16, P < .005), longer myocardial isovolumic relaxation time (57 ± 7 v 46 ± 12 msec, P < .05) as well as smaller myocardial E (10 ± 1 v 13 ± 2 cm/sec, P < .05) and E/A ratio (1.29 ± 0.25 v 1.78 ± 0.43, P < .05), despite similar LV mass (91 ± 16 v 93 ± 18 g/m2). Conclusion: Over a 5-year follow-up, initially lean, normotensive, young men with a moderate genetic risk for hypertension, developed Doppler echocardiographic alterations of LV diastolic function compared to matched offspring of normotensive parents. These alterations were more pronounced in the OHyp who developed mild hypertension and occurred without a distinct rise in LV mass. Am J Hypertens 2001;14:106-113 © 2001 American Journal of Hypertension, Lt

Sinusoidal small-signal (AC) and steady-state (DC) analysis of large-area solar cells

Beside fabrication challenges, efficiency loss factors of solar cells such as shunts and an increasing series resistance caused by the sheet resistance of the electrodes, are issues to be tackled when scaling novel photovoltaic devices up from laboratory to industrial size. We present a FEM (Finite Element Method) software that supports the upscaling process from small- to large-area devices. Considering Ohm’s law in the top and bottom electrodes, which are coupled by a vertical current, the software solves for the electric potential distribution in the 2D electrode domains. In addition to steady-state simulations, we introduce a small-signal analysis that allows us to compute the influence of resistive electrodes and defects on the frequency-dependent impedance response. Herein, we describe the implemented numerical model for the AC (alternating current) mode. The steady-state model was validated with measurements using monocrystalline silicon solar cells of several sizes and one cell was intentionally shunted with a laser to demonstrate the fingerprints of these defects in the DC (direct current) and AC response. In a further step, we verify the numerical simulation of the AC model with an analytical solution to a one-dimensional AC model for a simplistic quadratic domain and linearized coupling law. Overall, the presented AC model is able to reproduce and predict the behavior of the measurements of the original and later shunted silicon solar cell. Thereby we have demonstrated that the presented AC model is a powerful tool to study devices in the frequency domain which complements characterization in steady-state

Electro-thermal model for lock-in infrared imaging of defects in perovskite solar cells

The production of uniform layers without defects is crucial for the efficient upscaling of perovskite solar cells. To understand the origin of defects and their impact on efficiency, we compare steady-state (DC) and alternating current (AC) measurements with simulation results obtained by an electro-thermal 2D+1D finite element method (FEM) implemented in the software Laoss. The software supports the upscaling process from small- to large-area devices by solving for the potential and temperature distribution in 2D top and bottom electrode domains, which are coupled by a vertical 1D coupling law. Recently, we extended this FEM model to the frequency domain in order to study both DC and AC characteristics of solar cells. Here, we report on the extension of this frequency-dependent FEM model to the thermal domain, allowing us to calculate amplitude and phase images of solar cells that are voltagemodulated in the dark. We measured and modelled a screen-printed carbon-based hole-transporter-free perovskite solar cell with a defect, appearing as a hotspot in temperature measurements. In contrast to the traditional DLIT method using a large voltage modulation, we introduce a small-signal DLIT (SS-DLIT) imaging method which our model is capable to reproduce. Fitting thermal AC simulations to measured data, allowed to quantify the defect and examine its behaviour and origin

Exploring Late Bronze Age systems of bronzework production in Switzerland through Network Science

YesMany hundreds of Bronze Age bronze artefacts are known from excavations in Switzerland, yet the interpretation of production networks from the object find locations remain problematic. It is proposed that the decorative elements used on items, such as ring-jewellery, can be used as elements to assist in the identification of artisanal traditions and ‘schools’, and also regional or community preference and selection of specific designs. Combining the analysis of over 1700 items of ring-jewellery from Switzerland with approaches from network science has facilitated the identification of regional clustering of design elements, comparable with cultural typologies in the area. It is also possible to identify potential instances of cultural differentiation through decoration within the broader regional cultural traditions. The study highlights important facets of bronzework production in the region of Switzerland, while also demonstrating future potential directions which could build upon the European wide dataset of prehistoric bronzework.Primary research conducted under previous funding at University of Basel, Switzerland – SNF gran

NIM811, a Cyclophilin Inhibitor, Exhibits Potent In Vitro Activity against Hepatitis C Virus Alone or in Combination with Alpha Interferon

Host factors involved in viral replication are potentially attractive antiviral targets that are complementary to specific inhibitors of viral enzymes, since resistant mutations against the latter are likely to emerge during long-term treatment. It has been reported recently that cyclosporine, which binds to a family of cellular proteins, cyclophilins, inhibits hepatitis C virus (HCV) replication in vitro. Here, the activities of various cyclosporine derivatives were evaluated in the HCV replicon system. There was a strong correlation between the anti-HCV activity and cyclophilin-binding affinity of these compounds. Of these, NIM811 has been selected as a therapeutic candidate for HCV infection, since it binds to cyclophilins with higher affinity than cyclosporine but is devoid of the significant immunosuppressive activity associated with cyclosporine. NIM811 induced a concentration-dependent reduction of HCV RNA in the replicon cells with a 50% inhibitory concentration of 0.66 μM at 48 h. Furthermore, a greater than three-log(10) viral RNA reduction was achieved after treating the cells with as little as 1 μM of NIM811 for 9 days. In addition, the combination of NIM811 with alpha interferon significantly enhanced anti-HCV activities without causing any increase of cytotoxicity. Taken together, these promising in vitro data warrant clinical investigation of NIM811, an inhibitor of novel mechanism, for the treatment of hepatitis C

A collaborative hit-to-lead investigation leveraging medicinal chemistry expertise with high throughput library design, synthesis and purification capabilities.

High throughput screening (HTS) campaigns, where laboratory automation is used to expose biological targets to large numbers of materials from corporate compound collections, have become commonplace within the lead generation phase of pharmaceutical discovery. Advances in genomics and related fields have afforded a wealth of targets such that screening facilities at larger organizations routinely execute over 100 hit-finding campaigns per year. Often, 10(5) or 10(6) molecules will be tested within a campaign/cycle to locate a large number of actives requiring follow-up investigation. Due to resource constraints at every organization, traditional chemistry methods for validating hits and developing structure activity relationships (SAR) become untenable when challenged with hundreds of hits in multiple chemical families per target. To compound the issue, comparison and prioritization of hits versus multiple screens, or physical chemical property criteria, is made more complex by the informatics issues associated with handling large data sets. This article describes a collaborative research project designed to simultaneously leverage the medicinal chemistry and drug development expertise of the Novartis Institutes for Biomedical Research Inc. (NIBRI) and ArQule Inc.'s high throughput library design, synthesis and purification capabilities. The work processes developed by the team to efficiently design, prepare, purify, assess and prioritize multiple chemical classes that were identified during high throughput screening, cheminformatics and molecular modeling activities will be detailed