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91.
Dr. Christine Brotschi Dr. Martin H. Bolli Dr. John Gatfield Dr. Bibia Heidmann Dr. Francois Jenck Dr. Catherine Roch Dr. Thierry Sifferlen Dr. Alexander Treiber Dr. Jodi T. Williams Dr. Christoph Boss 《ChemMedChem》2020,15(5):430-448
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 (fu 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 . 相似文献
92.
Morpholine is a frequently used heterocycle in medicinal chemistry and a privileged structural component of bioactive molecules. This is mainly due to its contribution to a plethora of biological activities as well as to an improved pharmacokinetic profile of such bioactive molecules. The synthesis of morpholines is a subject of much study due to their biological and pharmacological importance, with the last such review being published in 2013. Here, an overview of the main approaches toward morpholine synthesis or functionalization is presented, emphasizing on novel work which has not been reviewed so far. This review is an update on synthetic strategies leading to easily accessible libraries of bioactives which are of interest for drug discovery projects. 相似文献
93.
在经济日益开放发展的今天,设计在人们的生活中充当了重要的角色。设计的产品是人造物的产品,人类根据自身的生活方式,行为习惯设计制造出为人类提供便利的产品,这些产品是基于人类对于自然的认识进而模仿或通过模仿继而创造出来的产物。本文基于人造物的分析,通过对于象的理解及现代设计的研究,其中对于 "观象制器"以及创新创造设计方法的理解及运用,为现代设计的提供指导方法,进而推动现代设计的发展。 相似文献
94.
Ensuring that the power system meets demand peaks is a key challenge of liberalized markets. On the supply side, capacity can be supported through a Capacity Remuneration Mechanism (CRM). On the demand side, Demand Response (DR) technologies can be deployed. We find that while all traditional generation should receive the same payment, capacity payments for DR technologies should gradually decrease based on operators’ position in the load-shedding order. We observe that all CRM schemes currently implemented provide inadequate incentives to non-price responsive DR and propose to adjust payments to DR units as a function of their expected activation periods. 相似文献
95.
Mostafa Dellahi Hattab Maker Guillermo Botella Enrique Alameda-Hernandez Azeddine Mouhsen 《International Journal of Circuit Theory and Applications》2020,48(6):887-905
The three-phase four-wire shunt active power filter (SAPF) was developed to suppress the harmonic currents generated by nonlinear loads, and for the compensation of unbalanced nonlinear load currents, reactive power, and the harmonic neutral current. In this work, we consider instantaneous reactive power theory (PQ theory) for reference current identification based on the following two algorithms: the classic low-pass filter (LPF) and the second-order generalized integrator (SOGI) filter. Furthermore, since an important process in SAPF control is the regulation of the DC bus voltage at the capacitor, a new controller based on the Lyapunov function is also proposed. A complete simulation of the resultant active filtering system confirms its validity, which uses the SOGI filter to extract the reference currents from the distorted line currents, compared with the traditional PQ theory based on LPF. In addition, the simulation performed also demonstrates the superiority of the proposed approach, for DC bus voltage control based on the Lyapunov function, compared with the traditional proportional-integral (PI) controller. Both novel approaches contribute towards an improvement in the overall performance of the system, which consists of a small rise and settling time, a very low or nonexistent overshoot, and the minimization of the total harmonic distortion (THD). 相似文献
96.
基于构建的裂纹剥离扩展失效过程的模拟方法,提出了预测临界载荷的方法,并通过界面的临界应变能释放率与损伤起始应力,构建了预防界面裂纹剥离扩展失效的等值临界真空压力约束预防控制线和设计准则。结果表明,临界压力载荷受控于界面初始预裂纹长度、复合界面的临界应变能释放率(GIC)和损伤起始应力(T0),与界面初始预裂纹长度呈负关联关系,而与临界应变能释放率与损伤起始应力呈正关联关系;当初始预裂纹长度由11.11 %增至15.55 %时,临界压力载荷(Pc)由87.6 kPa降至为57 kPa,降幅为34.9 %;内衬界面剥离韧性参数(T0,GIC)的坐标点位于等值临界真空压力约束控制线之上,可有效预防内衬界面剥离扩展失效。 相似文献
97.
Hashim A.
Hashim 《国际强度与非线性控制杂志
》2020,30(10):3848-3870
》2020,30(10):3848-3870
This paper introduces two novel nonlinear stochastic attitude estimators developed on the Special Orthogonal Group with the tracking error of the normalized Euclidean distance meeting predefined transient and steady‐state characteristics. The tracking error is confined to initially start within a predetermined large set such that the transient performance is guaranteed to obey dynamically reducing boundaries and decrease smoothly and asymptotically to the origin in probability from almost any initial condition. The proposed estimators produce accurate attitude estimates with remarkable convergence properties using measurements obtained from low‐cost inertial measurement units. The estimators proposed in continuous form are complemented by their discrete versions for the implementation purposes. The simulation results illustrate the effectiveness and robustness of the proposed estimators against uncertain measurements and large initialization error, whether in continuous or discrete form. 相似文献
98.
99.
Sawarot Phetsuk Robert Molloy Kanarat Nalampang Puttinan Meepowpan Paul D Topham Brian J Tighe Winita Punyodom 《Polymer International》2020,69(3):248-256
Understanding the underlying role of microstructural design in polymers allows for the manipulation and control of properties for a wide range of specific applications. As such, this work focuses on the study of microstructure–property relationships in l‐ lactide/?‐caprolactone (LL/CL) copolymers. One‐step and two‐step bulk ring‐opening polymerization (ROP) procedures were employed to synthesize LL/CL copolymers of various compositions and chain microstructures. In the one‐step procedure, LL and CL were simultaneously copolymerized to yield P(LL‐stat‐CL) statistical copolymers. In the two‐step procedure, poly(l‐ lactide) (PLL) and poly(?‐caprolactone) (PCL) prepolymers were synthesized in the first step before CL and LL respectively were added in the second step to yield P[LL‐b‐(CL‐stat‐LL)‐b‐LL] and P[CL‐b‐(LL‐stat‐CL)‐b‐CL] block copolymers as the final products. The findings reveal that, in addition to the copolymerization procedure employed, the length and type of the prepolymer play important roles in determining the chain microstructure and thereby the overall properties of the final copolymer. Moreover, control over the degree of crystallinity and the type of crystalline domains, which is controlled during the polymer chemistry process, heavily influences the physical and mechanical properties of the final polymer. In summary, this work describes an interesting approach to the microstructural design of biodegradable copolymers of LL and CL for potential use in biomedical applications. © 2019 Society of Chemical Industry 相似文献
100.
Surface-activated bonding (SAB), also called room-temperature bonding, is used in three-dimensional integration technology for semiconductor devices. An Ar fast atom beam (FAB) is used for SAB. However, conventional FAB guns must be replaced after hundreds of minutes of irradiation because carbon abrasion powders are generated by Ar ions sputtering in the gun. Therefore, this study develops a novel FAB gun with improved lifetime. The proposed FAB gun applies magnetic fields to guide Ar ions to reduce sputtering in the gun and improve irradiation efficiency. The proposed FAB gun indicates the possibility of improving gun lifetime. 相似文献