Global ETD Search
Search theses and dissertations gathered from participating repositories worldwide. Every result links back to the library that holds it. No account is needed.
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Showing 1 to 20 of 24 for “"lead optimization"”.
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Metabolic Stability And Pharmacokinetics In Lead Optimization Of Potential Anti-Psychostimulant Pharmacotherapies
… causing severe medical complications it also leads to several socioeconomic problems like healthcare expenditures, lost earnings and increase in drug-related crime. The discovery and development of potential pharmacotherapies to treat cocaine dependence has been a high priority for more than …
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A Pharmacokinetics and Pharmacodynamics (PK/PD) Guided Approach to Lead Optimization of Nitrofuranylamide Anti-Tuberculosis Agents
… (PK/PD) guided approach would facilitate the optimization of nitrofuranylamide lead compounds suitable for further development. </p> <p> First, we examined the biopharmaceutic properties and preclinical PK of nitrofuranylamide lead compounds. The first tested lead compound, Lee 562, exhibited …
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Application of process analysis and optimization tools in hit-to-lead and lead optimization phases of drug discovery at EPP, NIBR
… to notice the opportunity of introducing process optimization tools, such as Lean and Six Sigma, which showed success in manufacturing environments,. This project analyzes the interrelation between process and results, providing a clear explanation of cause and effect conditions, and a concise …
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Part A: Antimalarial agents modified at the C-16 position of artemisinin; Part B: Lead optimization of falcipain-2 and falcipain-3 inhibitors
… oral bioavailability will be improved. Part B: Lead Optimization of Falcipain-2 and Falcipain-3 Inhibitors. The expanding usage of artemisinin combination therapy casts concern about the potential development of drug resistance to this drug family, thus the search for new drug targets is always …
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Antimycobacterial 2-aminoquinazolinones and benzoxazole-based oximes: synthesis, biological evaluation, physicochemical profiling and supramolecular derivatization
… treatment duration. This study focused on hit-to-lead optimization of two new classes of compounds with potential anti-TB properties: 2-aminoquinazolinones (AQZs) and benzoxazole-based oximes (BZOs). A hit compound for each of these classes with low micromolar antimycobacterial activity had …
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Portfolio optimization in early drug R&D : a deeper dive into underlying dynamics of early research in pharmaceutical/biotech sector
… launch. Despite this uncertainty, senior leaders must make decisions about R&D portfolio, the impact of which may not be observable for many years. Hence the purpose of this thesis is to understand the current state of Pharmaceutical R&D portfolio management and identify the gaps in R&D …
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The design and synthesis of a new lead against tuberculosis
… scaffold as a potential candidate for optimization, which has a feasible synthetic route and is amenable to library generation to effectively explore local chemical space. Biological screening of the prepared compounds resulted in the identification of some compounds expressing …
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Improving ligand discovery using deep learning on three-dimensional structural data
… that are fundamental in hit identification and lead optimization. In this thesis, I first introduce existing deep learning applications in drug discovery, emphasizing on structure-based 3D generative models that produce molecules based on binding pocket context for high-affinity molecule …
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The Discovery and Development of Thienopyrimidines as Inhibitors of Helicobacter pylori
… elements of the two scaffolds. The resulting leads, including compound 25, demonstrate high potency with an acceptable cytotoxicity profile against the human FaDu cells. Mode of action studies were performed by the generation and sequencing of resistant mutants. These experiments identified H. …
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BIOLOGICAL AND TRANSDUCTIONAL EFFECTS OF ALLOSTERIC ANTAGONISTS ON THE ACTIVITY OF CHEMOATTRACTANT RECEPTORS
… CXCR1 and CXCR2 and was derived from a specific lead optimization program (Moriconi et al., 2007). Because it blocks both CXCR1 and CXCR2, it may overcome the problem of redundancy generated by the ELR+ CXC chemokine-CXCR1/R2 axis. The present study demonstrated, that DF 2156A is a potent blocker …
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Computer-Aided Drug Discovery for Helicobacter pylori
… of our diverse chemical library and for hit-to-lead optimization to find novel and narrow-spectrum Hp inhibitors.</p>
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Discovery and optimization of inhibitors and probes that target New Delhi metallo-[beta]-lactamase
… The use of hypothesis-driven screening and lead optimization that led to the discovery of novel irreversible covalent inhibitors of NDM is reported. Furthermore, the development and characterization of a reversible fluorescent probe that can be used to monitor the dynamic metalation, …
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INTEGRATION OF QUANTUM-MECHANICAL AND MOLECULAR DOCKING APPROACHES IN GLOBAL METHODS FOR METABOLISM PREDICTION OF XENOBIOTICS
… can be used to identify new hits and for hit-to-lead optimization in the early stages of the drug discovery process. Overall, these two strategies can be seen as complementary and particularly useful during the preclinical phase. The lack of highly accurate metabolic resources hampers the …
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Computer-aided design and synthesis of 5,7-dihydroxyflavone derivatives as glycogen phosphorylase inhibitors
… relationship analysis can help further guide lead optimization alongside pharmacokinetics and in vivo studies, until we can achieve a more potent and drug-like inhibitor of glycogen phosphorylase for the treatment of type 2 diabetes.
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Systems level characterizations of single and combination drug mechanisms of action in vitro and in vivo
… synthesis libraries generate more pharmaceutical leads than can be characterized in detail. Lead optimization further generates many derivatives of these cytotoxic hits in an attempt to generate optimized compounds with better physical or chemical properties. This leaves many promising agents …
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Computational Approaches To Anti-Toxin Therapies And Biomarker Identification
… substrates. These experiments were combined with lead optimization techniques to create a potent irreversible inhibitor which protects 95% of cells in vitro. Dynamics studies on a TcdB cysteine protease domain were performed to an allosteric communication pathway. Comparative analysis of the …
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Structure-Guided Design of Novel Therapeutics Targeting Translesion DNA Synthesis and Lipid A Biosynthesis
… to delineate a cryptic inhibitor envelope for optimization of a small molecule inhibitor of LpxC, an enzyme essential to the survival of Gram-negative bacteria. The resulting inhibitor shows vast improvement over its parent compound over a wide range of bacterial orthologs. </p><p>In summary, …
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Application of continuous improvement methodologies and techniques in the Drug Design Cycle
Amgen, one of the world's leaders in biotechnology, is currently investing in ways to better serve its patients by providing new drugs sooner, and to ensure its competitiveness for years to come. One way is to increase the efficiency within Research & Development (R&D), specifically within the Drug …
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Preclinical Study of Potential Antiglioma Novel Tetrahydroisoquinoline Analogs: Pharmacokinetics and Mechanism of Action
… drug metabolism/pharmacokinetics (DMPK)-guided lead optimization. EDL-291 was result from structure modification of last generation compound EDL-155. Its preclinical pharmacokinetics were characterized in this dissertation project. In male Sprague Daley (SD) rats, after 10 mg/kg intravenous …
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Structure-Based Drug Design in Medicinal Chemistry I. Development of Translesion Synthesis Inhibitors II. Synthesis and Biological Evaluation of Sulfonyl Piperazine Derivatives for LpxH Inhibition
<p>The identification of a promising lead compound is a crucial step for the drug development. Despite of a number of approaches, the optimization of promising hit compounds is still challenging. Structure-based drug design approach is a well established and widely used strategy based on the 3D …
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