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Lead Optimization (lead + optimization)
Selected AbstractsStandardization Protocols and Optimized Precursor Sets for the Efficient Application of Automated Parallel Synthesis to Lead Optimization: A Mitsunobu Example.CHEMINFORM, Issue 5 2003Robert G. Gentles Abstract For Abstract see ChemInform Abstract in Full Text. [source] Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic propertiesJOURNAL OF APPLIED TOXICOLOGY, Issue 3 2009Sebastian Polak Abstract The assessment of the torsadogenic potency of a new chemical entity is a crucial issue during lead optimization and the drug development process. It is required by the regulatory agencies during the registration process. In recent years, there has been a considerable interest in developing in silico models, which allow prediction of drug,hERG channel interaction at the early stage of a drug development process. The main mechanism underlying an acquired QT syndrome and a potentially fatal arrhythmia called torsades de pointes is the inhibition of potassium channel encoded by hERG (the human ether-a-go-go-related gene). The concentration producing half-maximal block of the hERG potassium current (IC50) is a surrogate marker for proarrhythmic properties of compounds and is considered a test for cardiac safety of drugs or drug candidates. The IC50 values, obtained from data collected during electrophysiological studies, are highly dependent on experimental conditions (i.e. model, temperature, voltage protocol). For the in silico models' quality and performance, the data quality and consistency is a crucial issue. Therefore the main objective of our work was to collect and assess the hERG IC50 data available in accessible scientific literature to provide a high-quality data set for further studies. Copyright © 2008 John Wiley & Sons, Ltd. [source] Design and Synthesis of a Focused Library of Novel Aryl- and Heteroaryl-KetopiperazidesARCHIV DER PHARMAZIE, Issue 12 2004Matthias Gerlach Abstract 1-Phenyl-4-piperazinyl-carbonyl-substituted nitrogen-containing heterocycles were discovered at Zentaris as a new class of potent, synthetic, small molecule tubulin inhibitors with strong antiproliferative activity. The lead structure of this class, D-24203, proved to be a potent inhibitor of in vivo tumor growth in different xenograft models including mammary and renal cancers. As part of our efforts in the lead optimization process to expand structural diversity as well as to optimize bioavailability parameters such as solubility and metabolic stability for these compounds, we produced and evaluated a focused library containing 320 compounds. Five new heterocyclic compound classes with comparable activity properties in the cytotoxicity and tubulin polymerization assay could be identi fied. In silico calculated bioavailability parameters for selected library members provides new compound classes with improved solubility properties. Library design, development of adequate solution phase methodology, and synthesis will be presented, as well as results of lead optimization. [source] Efficient Synthesis of Solasodine, O -Acetylsolasodine, and Soladulcidine as Anticancer Steroidal AlkaloidsCHEMISTRY & BIODIVERSITY, Issue 1 2007Xiaoming Zha Abstract An efficient synthesis of the steroidal alkaloids solasodine (1), O -acetylsolasodine (2), and soladulcidine (3) starting from easily available diosgenin and tigogenin in five or six steps (overall yield 25, 24, and 28%, resp.) is described. Moreover, our synthetic route provides a selective modification at C(3) of 1 and related compounds in order to carry out lead optimization on these natural antitumor steroidal alkaloids. [source] | ||||||||||