Automation of Synthesis in Medicinal Chemistry: Progress and Challenges.

Since the 1990s, concerted attempts have been made to improve the efficiency of medicinal chemistry synthesis tasks using automation. Although impacts have been seen in some tasks, such as small array synthesis and reaction optimization, many synthesis tasks in medicinal chemistry are still manual. As it has been shown that synthesis technology has a large effect on the properties of the compounds being tested, this review looks at recent research in automation relevant to synthesis in medicinal chemistry. A common theme has been the integration of tasks, as well as the use of increased computing power to access complex automation platforms remotely and to improve synthesis planning software. However, there has been more limited progress in modular tools for the medicinal chemist with a focus on autonomy rather than automation.

Rapid discovery of a novel series of Abl kinase inhibitors by application of an integrated microfluidic synthesis and screening platform.

Drug discovery faces economic and scientific imperatives to deliver lead molecules rapidly and efficiently. Using traditional paradigms the molecular design, synthesis, and screening loops enforce a significant time delay leading to inefficient use of data in the iterative molecular design process. Here, we report the application of a flow technology platform integrating the key elements of structure-activity relationship (SAR) generation to the discovery of novel Abl kinase inhibitors. The platform utilizes flow chemistry for rapid in-line synthesis, automated purification, and analysis coupled with bioassay. The combination of activity prediction using Random-Forest regression with chemical space sampling algorithms allows the construction of an activity model that refines itself after every iteration of synthesis and biological result. Within just 21 compounds, the automated process identified a novel template and hinge binding motif with pIC50 > 8 against Abl kinase--both wild type and clinically relevant mutants. Integrated microfluidic synthesis and screening coupled with machine learning design have the potential to greatly reduce the time and cost of drug discovery within the hit-to-lead and lead optimization phases.

Integrated Synthesis and Testing of Substituted Xanthine Based DPP4 Inhibitors: Application to Drug Discovery.

A novel integrated discovery platform has been used to synthesize and biologically assay a series of xanthine-derived dipeptidyl peptidase 4 (DPP4) antagonists. Design, synthesis, purification, quantitation, dilution, and bioassay have all been fully integrated to allow continuous automated operation. The system has been validated against a set of known DPP4 inhibitors and shown to give excellent correlation between traditional medicinal chemistry generated biological data and platform data. Each iterative loop of synthesis through biological assay took two hours in total, demonstrating rapid iterative structure-activity relationship generation.

Lead Diversification 2: application to P38, gMTP and lead compounds.

Lead Diversification is a new technology platform developed at Pfizer for the functionalization of drug molecules using C-H activation. We describe its application to some drug programs such as P38 and gMTP and the development of some new plate based screens including a fluorination screen.

Lead diversification. Application to existing drug molecules: mifepristone 1 and antalarmin 8.

A series of C-H functionalisation plate-based chemical screens and other C-H activation protocols were developed for the chemical diversification of drug molecules. In this Letter, metalloporphyrin and other catalytic oxidation systems are described in addition to chlorination. Mifepristone and antalarmin are used as substrates. The products obtained and the biological data demonstrate the potential utility of this approach.

Fully automated open access platform for rapid, combined serial evaporation and sample reformatting.

This paper reports a novel evaporator and its integration with an automated sample handling system to create a high throughput evaporation platform. The Vaportec V-10 evaporator uses a high speed rotation motor ( approximately 6000 rpm) to spin the vial containing a sample, creating a thin film of solvent which can be readily evaporated by the application of heat to the vial, while the consequent centrifugal force prevents "bumping". An intelligent algorithm controls pressure and temperature for optimum solvent removal conditions and end of run detection, critical for automation. The system allows the option of evaporation directly from a sample source vial, or alternatively, integrated liquid handling facilities provide the capability of transferring samples portionwise from a (large) source vial or bottle to a (small) daughter container, enabling efficient sample reformatting, with minimum user intervention. The open access system makes significant advances over current vacuum centrifugal evaporators in terms of evaporation rate and ease of automation. The evaporator's main features, the integration of robotics to provide automation, and examples of evaporation rates of a wide range of solvents from a variety of containers are described.