Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SAr reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.

Many workflows in Pharmaceutical R&D involve the manipulation of defined amounts of powders. Automated powder dispensing platforms are currently available; however, these existing technologies do not meet the requirements for every high-throughput experimentation powder dispensing application. A Working Group (WG) composed of pharmaceutical researchers within the Enabling Technologies Consortium (ETC) evaluated automated platforms commercially available from three manufacturers using an objective, systematic testing protocol. This paper describes the selection of powders and testing conditions used in this evaluation, and it assesses the impact that the powders, testing conditions, equipment environment, and other factors had on the performance of the selected platforms.

An automated high throughput screening approach to optimizing strong base-mediated metalations.