The Power of High-Throughput Experimentation: Case Studies from Drug Discovery, Drug Development, and Catalyst Discovery (Volume 2)

Rapid exploration of chemical space in Medicinal Chemistry projects is a demanding exercise that requires a steadfast approach and commitment to synthetic strategies that increase the success rate for desired compounds to answer a hypothesis. High-Throughput Experimentation (HTE) has proven to increase this success rate by directly evaluating project intermediates with pharmaceutically relevant building blocks in microscale quantities across a diverse chemical reaction space in parallel. This approach enables both the synthesis route and a blueprint for the scalability of the successful reactions. Herein, we present examples of the application of High-Throughput Chemistry (HTC) to Medicinal Chemistry projects spanning route scouting, parallel synthesis, and HTE coupled with other technologies such as flow and automation.

The rapid synthesis of a desired molecule is essential to meeting tight discovery timelines and to keep a medicinal chemistry project moving smoothly through the discovery design cycle. Identifying enabling reaction conditions using high-throughput experimentation (HTE) has been transformative to this process. Herein, the application of HTE to the synthetic chemistry challenges encountered in discovery chemistry is illustrated through the description of three use case studies from the Advanced Chemistry Technologies group at Abbvie.

This chapter details strategies toward developing library amenable reactions with a lens toward accessing a diverse array of medicinal chemistry targets using microscale or nanoscale techniques. These examples highlight the power of high-throughput experimentation (HTE) to rapidly elucidate the scope and limitations of synthetic methods and inspire targeted innovations to enhance the applicability of these transformations. Furthermore, the chapter highlights the state-of-the-art automation, analytical and software platforms for the efficient, and material sparing implementation of HTE to accelerate the design-make-test cycle.

The impact of high throughput experimentation to access significant diversity in enzyme sequence space in a single experiment has been revolutionizing the industrial application of biocatalysis in the past decade. A biocatalysis platform that is equipped to exploit the benefits of HTE is described herein and examples of how it has been used to find rapid and elegant solutions to synthetic applications translatable from early stage to late-stage chemistries are discussed.

This chapter describes the GSK workflow for high-throughput experimentation (HTE) evaluation of heterogeneous hydrogenation reactions and validation of results through the case study of a selective nitro reduction in the presence of an aryl chloride. Rapid mitigation of unexpected results on scale-up to deliver an acceptable process for pilot plant is addressed.

Privileged structures exhibiting good drug-like properties are recurring in a wide range of biologically active compounds for various pharmaceutical targets. This chapter aims to showcase the recent examples in highlighting high throughput experimentation (HTE) as a powerful tool to expedite the development of new synthetic methods for improved access to privileged structural motifs across the complete spectrum of the drug discovery and development continuum.

Peptide therapeutics have been termed the “Goldilocks” modality, possessing the target selectivity of a biologic coupled with the pharmacokinetics and biopharmaceutical properties akin to a small molecule, allowing the development of therapies that target traditionally “undruggable” space such as protein-protein interactions (PPI). Despite the promise that peptide therapeutics hold, they have remained a largely underexplored modality; however, advancements in synthetic organic chemistry and biotechnology platforms for hit-generation has incurred a revival, with FDA approvals of peptide therapeutics steadily increasing over the past 20 years. At the center of it all is high-throughput experimentation which has furthered peptide drug discovery through the generation of large and diverse peptide libraries that allow the interrogation of both structure and function.

This chapter encompasses an overview of the chemistry of methane (CH₄) functionalization and its intersection with high throughput experimentation (HTE) techniques. Heterogeneous and homogeneous CH₄ functionalization catalysts utilizing HTE in their experimental design are reviewed. This is followed by discussion of how academic and industrial laboratories alike can both benefit from the implementation of HTE techniques for efficient and cost-effective design of the next generation of CH₄ activation and functionalization catalysts.

Carboxylic acid derivatives such as acid chlorides, anhydrides, and thioesters are well established reaction partners in cross-coupling reactions, providing a milder alternative to traditional acyl substitution chemistry. Activation of robust and abundant esters is more challenging due to the relatively high strength of the C(acyl)–O bond. This chapter describes our group’s progress in expanding the utility of transition metal catalyzed ester activation facilitated by using high throughput experimentation to discover new catalysts and coupling partners

Herein we will discuss how HTE can facilitate not only the development of new reaction manifolds, but also how to design HTE experiments to gain further understanding useful in medicinal chemistry efforts and late-stage functionalization. Case studies on cobalt-catalyzed C–H methylation and iridium-catalyzed C–H amination using drugs as substrates are presented. Moving towards more sustainable ways of working in drug discovery we also showcase how new dispensing techniques can considerably add to miniaturization of reaction development.