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1.
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
2.
Praveen C. Ramamurthy Ashwini N. Mallya Alex Joseph William R. Harrell Richard V. Gregory 《Polymer Engineering and Science》2012,52(8):1821-1830
High molecular weight polyaniline (PANI) was synthesized by a combined procedure incorporating various synthesis methods. Temperature and open circuit potential of the reaction mixture were collected to monitor the reaction progress. The polymer is characterized by various techniques including gel permeation chromatography, dynamic light scattering, infrared spectroscopy, solid‐state nuclear magnetic resonance, and differential scanning calorimetry for elucidating the molecular architecture obtained by this method. As‐synthesized PANI was found to possess high molecular weight, reduced branching, reduced cross‐linking, and to predominantly consist of linear polymer chains. This polymer was also found to be more stable in solution form. J–V characteristics of as‐synthesized PANI films indicate a high current density which is due to increased free pathways and less traps for the charge transport to occur in PANI films. POLYM. ENG. SCI., 2012. © 2012 Society of Plastics Engineers 相似文献
3.
4.
RA Isoardi DW Townsend CS Carter A Herbster MA Dachille CC Meltzer 《Canadian Metallurgical Quarterly》1999,9(1):145-153
The success of the 15O-water PET technique to localize statistically significant changes in regional cerebral blood flow is dependent on factors such as the activity level injected and the magnitude of the flow change. Undetectable changes may occur if insufficient activity is injected leading to high levels of statistical noise or the task performed results in only small changes in blood flow. To explore the relationship between injected activity and statistical significance, we performed a series of studies with the ECAT EXACT HR+, a high resolution PET tomograph. A parametric verbal working memory task (the N-back task) was selected to examine the relationship between regional cerebral blood flow and working memory load across a range of injected doses of 15O-water. At each activity level the volunteers were required to perform four different levels of the N-back task, a task in which a letter displayed on a monitor is matched with the letter displayed N letters previously. With increasing N, this task places increased load on working memory. For this study, 5, 10, and 15 mCi of 15O-water were injected into nine normal volunteers. The complete sequence of four tasks (N = 0, 1, 2, and 3) at three activity levels was repeated twice, for a total of 24 injections of 15O-water. We show that the peak count rate performance for the HR+ is approached at injected activity levels of 15O-water around 15 mCi. For this particular choice of N-back task, robust activation maps can nevertheless be obtained with as little as 5 mCi injected dose. 相似文献
5.
BACKGROUND: Previous studies questioned the link between early childhood anemia and detrimental child development. OBJECTIVE: A population-based study was conducted to examine the association between early childhood anemia and mild or moderate metal retardation at 10 y of age. DESIGN: The present study linked early childhood nutrition data collected by the Special Supplemental Program for Women, Infants, and Children (WIC) and school records. Hemoglobin values were used to determine the relation between anemia in early life and children's placement in special education classes for mild or moderate mental retardation. Subjects were all participants in the WIC program. A computer program was used to link data from birth, WIC, and school records. RESULTS: Logistic regression showed an increased likelihood of mild or moderate mental retardation associated with anemia, independent of birth weight, maternal education, sex, race-ethnicity, the mother's age, or the child's age at entry into the WIC program. CONCLUSION: These findings support the proposition that efforts to prevent mild and moderate mental retardation should include providing children with adequate nutrition during early childhood. 相似文献
6.
E. Harrell Ray Rabeh H. Elleithy Coleen A. McFarland James W. Summers 《乙烯基与添加剂工艺杂志》1999,5(3):116-124
The viscoelastic nature of PVC cannot be ignored during the injection molding process. Strains imposed on the compound during the injection stage display recovery dynamics that are indicative of the temperature at which the strains were imposed. A mathematical model, employing “approximate” time-temperature modulus relationships, provided the basis for interpreting the shrinkage data. A distribution map of the various relative temperatures attained within the part during injection was determined. 相似文献
7.
1月,备受关注的年度大戏《孔子》将亮相荧屏。在其中饰演霓裳的李欣汝,一个从古典舞中走出的女子,形神兼具的身韵翩然跳出最优美的舞姿,带你进入千年以前,那个烽火连天却笙箫依旧的春秋战国,领略中华名族的根髓。 相似文献
8.
CC Nadelson 《Canadian Metallurgical Quarterly》1976,14(3):124-127
Adopted children are emotionally vulnerable. Adoptive parents must cope with more complex problems than biologic parents. The family physician can provide valuable counseling. Preadoption counseling focuses on motivation and ambivalence. After adoption, however, serious, sometimes predictable, issues arise, such as: how and when to tell the child he is adopted; the child's search for knowledge; the problem of subsequent divorce; the birth of a natural sibling, and the involvement of other family members. New concepts include "open adoption" and "single parent adoption." 相似文献
9.
The concept of cardiac reconditioning centers for the prevention and rehabilitation of coronary patients has been tremendously successful in Germany over the past 20 years. At least 40 such centers are located throughout the country. Physicians, nurses, and physical therapists work closely together in the various facets of the rehabilitation process. The financial backing for these facilities is primarily through governmental and regional insurance companies, whose officials are apparently convinced that in the long run supporting preventive measures is financially sound. Objective data supporting their convictions come from studies such as that of Brusis, who showed that such as that of 1,500 employees was diminished by nearly 70 percent during a two-year period after cardiac reconditioning, as compared to a similar time period before the rehabilitation experience. Subjective benefits, which are extremely difficult to quantitate in meaningful terms, were nonetheless expressed by nearly all the patients with whom I conversed. Perhaps they have experienced the same feelings that Mark Twain did when he observed that "all frets and worries and chafings sank to sleep in the presence of the benignant serenity of the Alps; the Great Spirit of the Mountains breathed his own peace upon their hurt minds and sore hearts and healed them." 相似文献
10.
The effect of actinomycin-D (AMD) on radiation damage repair was studied in plateau phase V79 Chinese hamster cells. Sublethal radiation damage repair, as demonstrated by survival fluctuations following two x-ray exposures separted by time, was observed in our plateau phase cells. Plateau phase cells exposed to 0.01-0.04 mug/ml AMD (a nontoxic regimen to 8 hours) between x-ray exposures were less able to repair sublethal damage. If plateau phase cells were plated at low dilutions into fresh medium (conditions for resuming exponential growth) immediately after the first x-ray dose, and exposed to 0.01--0.04 mug/ml AMD until the second dose, inhibition of sublethal damage repair and additional cell killing were observed particularly at 0.04 mug/ml AMD. It is suggested that radiation-drug damage interactions should be studied in plateau phase cells and in cells resuming exponential growth after plateau phase (possibly analogous to "recruitment"), as well as in exponential phase cultures. 相似文献