Pyrimidines

Publication Title: 
Drug Design, Development and Therapy

A recent explosion in the amount of cardiovascular risk and incipient, undetected subclinical cardiovascular pathology has swept across the globe. Nearly 70% of adult Americans are overweight or obese; the prevalence of visceral obesity stands at 53% and continues to rise. At any one time, 55% of the population is on a weight-loss diet, and almost all fail. Fewer than 15% of adults or children exercise sufficiently, and over 60% engage in no vigorous activity.

Author(s): 
Kones, Richard
Publication Title: 
Journal of Pharmaceutical Sciences

Several 1-aryl-3-(2-pyrimidyl)thiocarbamides and their corresponding cyclized 2-arylimino-3-(2-pyrimidyl)thiazolid-4-ones were synthesized and characterized by their sharp melting points and elemental analyses. These thiocarbamides and thiazolidones possessed anticonvulsant activity against pentylenetetrazol-induced convulsions and potentiated pentobarbital-induced hypnosis in mice. Most of these thiocarbamides and thiazolidones selectively inhibited nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate, where the use of added NAD dether hand, remained unaltered.

Author(s): 
Chaudhary, M.
Parmar, S. S.
Chaudhary, S. K.
Chaturvedi, A. K.
Sastry, B. V.
Publication Title: 
The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

Ketamine has important anesthetic, analgesic, and psychotropic actions. It is widely believed that NMDA receptor inhibition accounts for ketamine actions, but there remains a dearth of behavioral evidence to support this hypothesis. Here, we present an alternative, behaviorally relevant molecular substrate for anesthetic effects of ketamine: the HCN1 pacemaker channels that underlie a neuronal hyperpolarization-activated cationic current (I(h)).

Author(s): 
Chen, Xiangdong
Shu, Shaofang
Bayliss, Douglas A.
Publication Title: 
Planta Medica

The effects of annomontine, a pyrimidine- ?-carboline alkaloid isolated from the root of ANNONA PURPUREA, on anxiety was studied in mice using the elevated plus-maze. The behavioral effects of this alkaloid on the pentobarbital-induced hypnosis, the locomotor activity in an open field, and the motor coordination in the rotarod test were also evaluated. The intraperitoneal injection of annomontine (1-30 mg/kg) increased in a dose-dependent way the number of visits to and the time spent in the open arms of the elevated plus-maze in comparison to the control animals.

Author(s): 
Rejón-Orantes, José Del Carmen
González-Esquinca, Alma Rosa
de la Mora, Miguel Pérez
Roldan Roldan, Gabriel
Cortes, Diego
Publication Title: 
Behavioural Pharmacology

To characterize the sedative and hypnotic profile of the novel adenosine derivative ((3S,4R,5R)-3,4-dihydroxy-5-(6-((4-hydroxy-3-methoxybenzyl)amino)-9H-purin-9-yl)tetrahydrofuran-2-yl) methyl diaconate (WS0701), we performed a variety of behavioural tests and investigated the influence of WS0701 on various sleep stages. In mice, WS0701 significantly increased the number of entries and time spent in open arms in the elevated plus maze test, indicating an anxiolytic effect.

Author(s): 
Bai, Xiao-Yu
Zhang, Xue-Qiong
Zhang, Yong-He
Wu, Song
Hao, Ling-Hua
Liu, Rui
Huang, Zhong-Lin
Zhang, Wei-Ku
Sun, Zong-Miao
Du, Guan-hua
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

With >1 million deaths annually, mostly among children in sub-Saharan Africa, malaria poses one of the most critical challenges in medicine today. Although introduction of the artemisinin class of antimalarial drugs has offered a temporary solution to the problem of drug resistance, new antimalarial drugs are needed to ensure effective control of the disease in the future. Herein, we have investigated members of the methionine aminopeptidase family as potential antimalarial targets.

Author(s): 
Chen, Xiaochun
Chong, Curtis R.
Shi, Lirong
Yoshimoto, Tadashi
Sullivan, David J.
Liu, Jun O.
Publication Title: 
Antimicrobial Agents and Chemotherapy

Neurocysticercosis (NCC), an infection of the brain with the larval stage of the Taenia solium tapeworm, is responsible for an estimated one-third of adult-onset epilepsy cases in regions of the world where it is endemic. Currently, anthelmintic drugs used for treatment of NCC are only partially effective, and there is, therefore, a pressing need for new therapeutic agents. Discovery of new anthelmintics with activity against T. solium has been limited by the lack of suitable sensitive assays that allow high-throughput screening.

Author(s): 
Mahanty, Siddhartha
Madrid, Elise M.
Nash, Theodore E.
Publication Title: 
American Journal of Physiology. Endocrinology and Metabolism

An ethanolic extract of Russian tarragon, Artemisia dracunculus L., with antihyperglycemic activity in animal models was reported to decrease phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression in STZ-induced diabetic rats. A quantitative polymerase chain reaction (qPCR) assay was developed for the bioactivity-guided purification of the compounds within the extract that decrease PEPCK expression. The assay was based on the inhibition of dexamethasone-stimulated PEPCK upregulation in an H4IIE hepatoma cell line.

Author(s): 
Govorko, Dmitry
Logendra, Sithes
Wang, Yanxin
Esposito, Debora
Komarnytsky, Slavko
Ribnicky, David
Poulev, Alexander
Wang, Zhong
Cefalu, William T.
Raskin, Ilya
Publication Title: 
American Journal of Physiology. Heart and Circulatory Physiology

We recently reported that increased vascular endothelial nitric oxide production could protect against the development of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and right ventricular hypertrophy (RVH) in rats (32). The present study investigated whether the pleiotropic action of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in upregulating endothelial function could also protect against the MCT-induced end-organ damages. Rosuvastatin (2 mg kg(-1) day(-1) via oral gavage) or placebo was initiated 1 wk before or 1 wk after MCT (60 mg/kg ip) administration.

Author(s): 
Sun, Xiaowei
Ku, David D.
Publication Title: 
Clinical Cancer Research: An Official Journal of the American Association for Cancer Research

PURPOSE: To evaluate the effects of ritonavir, a potent inhibitor of CYP3A4, on the steady-state pharmacokinetics of imatinib. EXPERIMENTAL DESIGN: Imatinib pharmacokinetics were evaluated in cancer patients receiving the drug for at least 2 months, after which ritonavir (600 mg) was administered daily for 3 days. Samples were obtained on the day before ritonavir (day 1) and on the third day (day 4).

Author(s): 
van Erp, Nielka P.
Gelderblom, Hans
Karlsson, Mats O.
Li, Jing
Zhao, Ming
Ouwerkerk, Jan
Nortier, Johan W.
Guchelaar, Henk-Jan
Baker, Sharyn D.
Sparreboom, Alex

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