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Drug Discovery Program (drug + discovery_program)
Selected AbstractsPreparation of novel azabicyclic amines and ,7 nicotinic acetylcholine receptor activity of derived aryl amidesJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 1 2008Daniel P. Walker Three new azabicyclic amines, namely exo -3-amino-1-azabicyclo[3.2.1]octane, 3-amino-1-azabicyclo-[3.2.2]nonane and exo -6-amino-8-azabicyclo[3.2.1]octane, have been designed and prepared as isosteres of 3-aminoquinuclidine. Aryl amides derived from each series were prepared and tested in an ,7 nicotinic acetylcholine receptor assay as part of a drug discovery program to treat the cognitive deficits in schizophrenia. All new amides showed significant ,7 nAChR activity and one series displayed potent ,7 activity equal to the quinuclidine series. [source] Screening of antioxidant phenolic compounds in Chinese Rhubarb combining fast counter-current chromatography fractionation and liquid chromatography/mass spectrometry analysisJOURNAL OF SEPARATION SCIENCE, JSS, Issue 11 2010Ruilin Hu Abstract In this paper, an effective method combing fast elution-extrusion counter-current chromatography (CCC) and LC/MS for rapid screening of antioxidative phenolic compounds in Chinese Rhubarb is presented. An integrated three-coil CCC column (40,mL each coil) was used to accomplish the optimization of biphasic liquid system. In a single run (approximately 40,min), the solvent system composed of n -hexane/ethyl acetate/methanol/water (1:1:1:1, v/v) was selected as optimum CCC liquid system for fast fractionation of the crude ethanol extract. With a 140,mL-capacity CCC instrument, 100,mg Chinese Rhubarb extract was separated under the optimized conditions, producing six fractions in only 100,min. The quantities of each fraction were ,15,mg. In addition, each fraction was subjected to antioxidant activity assay and characterized by LC/MS analysis. Fifty compounds, including phenolic acids, phenolic glucosides and hydroxyanthraquinones, were detected by LC/MS/MS analysis. As a result, gallic acid together with Fr I showed excellent antioxidant activity, which was well consistent with previous studies and exhibited great potential for natural drug discovery program of the present method. [source] The development of an NMR chemical shift prediction application with the accuracy necessary to grade proton NMR spectra for identityMAGNETIC RESONANCE IN CHEMISTRY, Issue 12 2009Stephen G. Spanton Abstract We have developed an NMR chemical shift prediction system that enables high throughput automatic grading of NMR spectra. In support of high throughput synthetic efforts for our drug discovery program, a rapid and accurate analysis for identity was needed. The system was designed and implemented to take advantage of the NMR assignments that had been tabulated on internally generated research compounds. The system has been operational for four years and has been used in conjunction with an internally written grading program to successfully analyze several hundred thousand samples based only on their 1D 1H spectrum. A focused test of the system's accuracy on 1006 molecules demonstrated the ability to estimate the proton chemical shift with an average error of +/,0.16 ppm. This level of chemical shift accuracy allows for reliable structure confirmation by automated analysis using only proton NMR. Copyright © 2009 John Wiley & Sons, Ltd. [source] Phosphodiesterase 5 (PDE 5) inhibitors for the treatment of male erectile disorder: Attaining selectivity versus PDE6MEDICINAL RESEARCH REVIEWS, Issue 3 2006Dmitri Pissarnitski Abstract The role of phosphodiesterase type 5 (PDE5) in the mechanism of male erection has been well understood, and several drugs inhibiting this enzyme are being used for the treatment of erectile dysfunction (ED). Discovery of inhibitors with improved selectivity versus other PDE isozymes could lead to drugs with improved safety profile. Achievement of selectivity versus PDE6, co-inhibition of which results in disturbances of color perception, remains the most challenging aspect of current drug discovery programs. The present review describes several case studies, where significant (>100 fold) selectivity versus PDE6 has been attained via investigation of structure,activity relationships (SAR). Special attention is given to the chemical routes leading to novel chemotypes and allowing efficient exploration of their SAR's. Strategies for attaining inhibitor selectivity discussed below may be applicable for other drug discovery programs. © 2005 Wiley Periodicals, Inc. Med Res Rev [source] The mechanisms of tumor suppressor effect of glucocorticoid receptor in skinMOLECULAR CARCINOGENESIS, Issue 8 2007Dmitry Chebotaev Abstract Glucocorticoid hormones exert a tumor suppressor effect in different experimental models, including mouse skin carcinogenesis. The glucocorticoid control of cellular functions is mediated via the glucocorticoid receptor (GR), a well-known transcription factor that regulates genes by DNA-binding dependent transactivation, and DNA-binding independent transrepression through negative interaction with other transcription factors. In this perspective, we analyze known mechanisms that underlie the anticancer effect of GR signaling, including effects on cell growth, differentiation, apoptosis, and angiogenesis. We also discuss a novel mechanism for the tumor suppressor effect of the GR in skin: through the regulation of the number and status of follicular epithelial stem cells (SC), which are a target cell population for skin carcinogenesis. Our studies on keratin5.GR transgenic animals that are resistant to skin carcinogenesis, demonstrated that the GR diminishes the number of follicular epithelial SCs, reduces their proliferative and survival potential and affects the expression of follicular SC "signature" genes. The analysis of global effect of the GR on gene expression in follicular epithelial SCs, basal keratinocytes, and mouse skin tumors provided an unexpected evidence that gene transrepression by GR plays an important role in the maintenance of SC and in inhibition of skin carcinogenesis by this steroid hormone receptor. It is known that antiinflammatory effect of glucocorticoids is chiefly mediated by GR transrepression. Thus, our findings suggest the similarity between the mechanisms of antiinflammatory and anticancer effects of the GR signaling. We discuss the potential clinical applications of our findings in light of drug discovery programs focused on the development of selective GR modulators that preferentially induce GR transrepression. © 2007 Wiley-Liss, Inc. [source] Development of a Method for the High-Throughput Quantification of Cellular ProteinsCHEMBIOCHEM, Issue 10 2009Paolo Paganetti Dr. Abstract Hunting for huntingtin: We describe a screening assay based on the inducible expression of the mutant huntingtin protein in cells and on its highly sensitive homogenous determination. Rapid, reproducible, and robust protein determination was achieved through the use of two donor,acceptor-labeled antibodies and time-resolved FRET. The assay was developed and validated for ultra-throughput screening of low-molecular-weight compounds modulating the expression of the mutant protein. The quantification of cellular proteins is essential for the study of many different biological processes. This study describes an assay for the detection of the intracellular mutant huntingtin, the causative agent of Huntington's disease, with a method that may be generally applicable to other cellular proteins. A small recombinant protein tag that is recognized by a pair of readily available, high-affinity monoclonal antibodies was designed. This tag was then added to an inducible fragment of the mutant huntingtin protein by genetic engineering. We show that it is possible to use time-resolved FRET to detect low intracellular levels of huntingtin by a simple lysis and detection procedure. This assay was then adapted into a homogeneous, miniaturized format suitable for screening in 1536-well plates. The use of time-resolved FRET also permits the assay to be multiplexed with a standard readout of cell toxicity, thus allowing the identification of conditions causing reduction of protein levels simply due to cytotoxicity. The screening results demonstrated that the assay is able to identify compounds that modulate the levels of huntingtin both positively and negatively and that represent valuable starting points for drug discovery programs. [source] | ||||||||||