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71.
Discovery of 5′′‐Chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064): A Selective Orexin 2 Receptor Antagonist (2‐SORA) for the Treatment of Insomnia 下载免费PDF全文
Dr. Anthony J. Roecker Swati P. Mercer John D. Schreier Dr. Christopher D. Cox Dr. Mark E. Fraley Justin T. Steen Wei Lemaire Joseph G. Bruno C. Meacham Harrell Susan L. Garson Dr. Anthony L. Gotter Steven V. Fox Joanne Stevens Dr. Pamela L. Tannenbaum Dr. Thomayant Prueksaritanont Dr. Tamara D. Cabalu Dr. Donghui Cui Joyce Stellabott Dr. George D. Hartman Dr. Steven D. Young Dr. Christopher J. Winrow Dr. John J. Renger Dr. Paul J. Coleman 《ChemMedChem》2014,9(2):311-322
The field of small‐molecule orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the orexin peptides to clinical proof‐of‐concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the orexin 1 and orexin 2 receptors (OX1R and OX2R), termed dual orexin receptor antagonists (DORAs), affording late‐stage development candidates including Merck’s suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX1R or OX2R alone has been hampered by the dearth of suitable subtype‐selective, orally bioavailable ligands. Herein, we report the development of a selective orexin 2 antagonist (2‐SORA) series to afford a potent, orally bioavailable 2‐SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5‐disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P‐glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2‐SORA clinical candidate, 5′′‐chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064), in mouse, rat, dog, and rhesus sleep models. 相似文献
72.
Cristiane Franco Codevilla Tamara dos Santos Castilhos Carolina Araújo Cirne Pedro Eduardo Froehlich Ana Maria Bergold 《Drug development and industrial pharmacy》2014,40(4):488-493
Introduction: Lodenafil carbonate is a phosphodiesterase type 5 inhibitor used for the treatment of erectile dysfunction. Currently, there is no dissolution test reported for lodenafil carbonate and this drug is not listed in any pharmacopoeia.Objective: The present study focused on the development and validation of a dissolution test for lodenafil carbonate tablets, using a simulated absorption profile based on in vivo data.Methods: The appropriate conditions were determined after testing sink conditions. Different conditions as medium, surfactant concentration and rotation speed were evaluated. The percentage of dose absorbed was calculated by deconvolution, using the Wagner–Nelson method.Results: According to the obtained results, the use of 0.1?M HCl?+?1.5% SLS (900?mL, at 37?+?0.5?°C) as the dissolution medium, paddles at 25?rpm were considered adequate. The samples were quantified by UV spectroscopy at 295?nm and the validation was performed according to international guidelines. The method showed specificity, linearity, accuracy and precision, within the acceptable range. Kinetics of drug release was better described by the first-order model.Conclusion: The proposed dissolution test can be used for the routine quality control of lodenafil carbonate in tablets. 相似文献
73.
Sperm surface changes and physiological consequences induced by sperm handling and storage 总被引:1,自引:0,他引:1
Spermatozoa interact with their immediate environment and this contact remodels the sperm surface in preparation for fertilisation. These fundamental membrane changes will be critically covered in this review with special emphasis on the very specific surface destabilisation event, capacitation. This process involves very subtle and intricate modifications of the sperm membrane including removal of suppression (decapacitation) factors and changes in the lateral organisation of the proteins and lipids of the sperm surface. Processing of sperm for assisted reproduction (storage, sex-sorting, etc.) subjects spermatozoa to numerous stressors, and it is possible that this processing overrides such delicate processes resulting in sperm instability and cell damage. To improve sperm quality, novel mechanisms must be used to stabilise the sperm surface during handling. In this review, different types of membrane stress are considered, as well as novel surface manipulation methods to improve sperm stability. 相似文献
74.
Tamara Garcia-Armisen Ken VercammenJulien Passerat David TriestPierre Servais Pierre Cornelis 《Water research》2011,45(2):788-796
Sewage-contaminated rivers are ecosystems deeply disturbed by human activity due to the release of heavy metals, organic pollutants and pharmaceuticals as well as faecal and pathogenic micro-organisms, which coexist with the autochthonous microbial population. In this study, we compared the percentage of resistance in faecal and heterotrophic bacteria in rivers with different degrees of sewage pollution. As a matter of fact, no correlation was found neither between the degree of sewage pollution and the percentage of antimicrobial resistant heterotrophic bacteria nor between the number of resistant faecal bacteria and that of resistant heterotrophic bacteria. Most of the resistant isolates from the Zenne river downstream Brussels were multi-resistant and the resistance patterns were similar among the strains of each phylogenetic group. The total microbial community in this polluted river (as evaluated through a 16S rRNA gene clone library analysis) appeared to be dominated by the phyla Proteobacteria and Bacteroidetes while the phylum TM7 was the third most represented. 相似文献
75.
Batteries: Carbon‐Based Anodes for Lithium Sulfur Full Cells with High Cycle Stability (Adv. Funct. Mater. 9/2014) 下载免费PDF全文
76.
Jan Brückner Sören Thieme Falko Böttger‐Hiller Ingolf Bauer Hannah Tamara Grossmann Patrick Strubel Holger Althues Stefan Spange Stefan Kaskel 《Advanced functional materials》2014,24(9):1284-1289
The lithium sulfur battery system has been studied since the late 1970s and has seen renewed interest in recent years. However, even after three decades of intensive research, prolonged cycling can only be achieved when a large excess of electrolyte and lithium is used. Here, for the first time, a balanced and stable lithium sulfur full cell is demonstrated with silicon–carbon as well as all‐carbon anodes. More than 1000 cycles, a specific capacity up to 1470 mAh g?1 sulfur (720 mAh g?1 cathode), and a high coulombic efficiency of over 99% even with a low amount of electrolyte are achieved. The alternative anodes do not suffer from electrolyte depletion, which is found to be the main cause of cell failure when using metallic lithium anodes. 相似文献
77.
78.
Alexander A. Khassin Vladimir V. Pelipenko Tatyana P. Minyukova Vladimir I. Zaikovskii Dmitrii I. Kochubey Tamara M. Yurieva 《Catalysis Today》2006,112(1-4):143-147
The catalytic activity of CuZn catalysts in the synthesis of methanol is related to those reduced Cu species, which originate from the CuxZn1−xO solid solution of wurtzite-like structure. Copper cations in the CuxZn1−xO solid solution are localized in the extended stacking faults of the ZnO lattice. Copper sites could be supposedly described as the product of introducing (OH)Cu(OH) to the planar defects of zinc oxide structure. Hydroxyl groups stabilize the planar defects of ZnO. The process of the samples reduction leads to the formation of flat Cu0 particles over the surface of zinc oxide. The planar defects of ZnO structure are preserved in the reduced state. During the reoxidation, copper atoms return back to the extended stacking faults of ZnO as the tape-like clusters of flat-square coordinated copper cations. 相似文献
79.
Halle Tamara G.; Kurtz-Costes Beth; Mahoney Joseph L. 《Canadian Metallurgical Quarterly》1997,89(3):527
The authors examined the achievement-related beliefs and behaviors of parents of economically disadvantaged African American youth, and the relations among parental factors and children's academic self-concept and achievement. Forty-one children and their primary caregivers were interviewed. Parents reported on their academic-related beliefs and behaviors. Children completed measures of academic self-concept and 2 standardized achievement tests: 1 during the summer and 1 at the end of the following school year. Significant and positive relations were found between parental belief and behavior measures within the domains of reading and math; however, parental beliefs were more strongly linked with child outcomes than were parents' achievement-oriented behaviors. The relation between parental beliefs and child outcomes was not mediated by children's academic self-concept. Results are discussed in light of models of family influences on achievement. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
80.
Wall Tamara L.; Shea Shoshana H.; Luczak Susan E.; Cook Travis A. R.; Carr Lucinda G. 《Canadian Metallurgical Quarterly》2005,114(3):456
Associations of alcohol dehydrogenase (ADH) gene polymorphisms (ADH1B*2 and ADH1C*1) with a lifetime alcohol use disorder (AUD) were examined in White college students. Alcohol-related endophenotypes likely to be influenced by elevations in acetaldehyde were also assessed. Individuals with an ADH1B*2 allele had lower rates of AUDs, consumed a lower maximum number of drinks in a 24-hr period, reported a greater level of response to alcohol, were more likely to have experienced alcohol-induced headaches following 1 or 2 drinks, and reported more severe hangovers than those lacking this allele. These findings are consistent with the hypothesis that enhanced sensitivity to alcohol and lower levels of alcohol use reflect the mechanism by which ADH1B*2 protects against developing an AUD. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献