From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

The orexin system is responsible for regulating the sleep-wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}methanone ( 6 ), a compound which emerged from our in-house research program. Compound 6 was shown to be a potent, brain-penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (f_u brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above-mentioned shortcomings resulted in the identification of (4-chloro-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-methyl-2-[5-(2-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone ( 42 ), a DORA with improved in vivo efficacy compared to 6 .     

Nano-Design für Makroschichten

Nano design for macroscopic coatings – new application potentials by PVD coatings up to 100 μm thickness Non-homogeneous coatings still limit the application of thicker layers due to defect growth and irregular layer thickness distribution along the surface of complex shaped components. Therefore, the layer thickness is usually limited to about 10 μm. In order to limit the surface roughness by the growing layer, multilayer coating systems are deposited by highly ionized plasmas. This allows significantly smoother layers to be produced, which until now could only be produced by mechanical finishing. Furthermore, by combining selected material systems and targeted parameter selection, structures can be deposited during coating, especially on edges, which result in a reduction of the cutting edge radius. In future, edge geometries should therefore be able to be specifically adjusted through the coating process.     

A flexible air separation process: 1. Design and steady-state optimizations

The flexible operation of energy-intensive processes, such as cryogenic air separation, has economic potential due to increasing fluctuations of the electricity markets. Multiproduct air separation processes with high ratios of liquid product are very promising for flexible operation due to storable products. We present a process design with an integrated liquefication cycle and liquid assist operation, that facilitates a high liquid product ratio and a flexible process operation. We use a mechanistic dynamic process model in steady-state process optimizations covering the wide operational range of the proposed process. The optimization results show that the power demand can be varied in a range from 3.5 to 28 MW without violating operational constraints by changing the nitrogen and oxygen production rates. Thus, the proposed process is a promising air separation candidate for flexible operation with respect to fluctuating electricity markets.     

Recommender systems in the healthcare domain: state-of-the-art and research issues

Journal of Intelligent Information Systems - Nowadays, a vast amount of clinical data scattered across different sites on the Internet hinders users from finding helpful information for their...     

Endometriosis detection and localization in laparoscopic gynecology

Multimedia Tools and Applications - Endometriosis is a common gynecologic condition typically treated via laparoscopic surgery. Its visual versatility makes it hard to identify for non-specialized...