Synthesis of compound libraries via parallel or combinatorial synthesis requires the weighing and formatting of a large number of chemical reagents. Accurate reagent concentration determines the efficiency of the reactions. The structural information contained within the reagent vial barcode also translates into structural information for the product when liquid handling robots are utilized. It is therefore critical that structural and concentration related parameters be derived directly from the reagent database and encoded in the barcode with no human manipulations. The searching, weighing, and recording of structure and weights directly from the database is a labor intensive and errorprone process. There are tools and instruments in the market that can individually perform these tasks. However, none integrate all the components (balance, scanner, printer and database) together as a single automated weighing workbench. We have developed an automated weighing workbench that eliminates the potential for human errors, reduces the time it takes to weigh a reagent, and tracks the reagents through a live connection to a database.
Introducing a uniquely substituted phenyl sulfone into a series of biphenyl imidazole liver X receptor (LXR) agonists afforded a dramatic potency improvement for induction of ATP binding cassette transporters, ABCA1 and ABCG1, in human whole blood. The agonist series demonstrated robust LXRβ activity (>70%) with low partial LXRα agonist activity (<25%) in cell assays, providing a window between desired blood cell ABCG1 gene induction in cynomolgus monkeys and modest elevation of plasma triglycerides for agonist 15. The addition of polarity to the phenyl sulfone also reduced binding to the plasma protein, human α-1-acid glycoprotein. Agonist 15 was selected for clinical development based on the favorable combination of in vitro properties, excellent pharmacokinetic parameters, and a favorable lipid profile.
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