Chiral Scaffolds

Enantiomeric separation of privileged scaffold derivatives in early drug discovery using chiral SFC

Introduction

The early drug discovery process is resourceintensive, and for a variety of reasons the vast majority of HTS hits do not progress very far. Medicinal chemistry resources are critical to success, and often in great demand, especially when a strong candidate emerges and intense synthetic efforts are needed to identify a promising clinical candidate. Therefore, the hundreds to thousands of molecules emerging from HTS screening need to be efficiently prioritized and vetted. Filters are used to hone the numbers down to manageable quantities and one filter is chirality. Unlike achiral hits that consist of a single molecule, chiral hits consist of two enantiomers that can have dramatically different biological activity. As such, assay data for chiral mixtures is clouded by the activity of both molecules and thus does not reflect the activity of the individual enantiomers. Therefore, chiral hits are best studied as individual enantiomers which require the additional step of preparative separation. Statistics from the marketplace offer compelling reasons to invest in this extra effort. For example, of the 30 top selling drugs in 2014, 40% were chiral, while only 13% were achiral [the remaining 47% were therapeutic proteins or antibodies (1)]. Similarly, of the 40 most promising clinical candidates that were in development in 2016, more than 38% were chiral (2).

To address the need to purify chiral molecules at early stages of drug discovery, many large pharmaceutical companies have developed in-house capabilities for chiral separations (3, 4). However, smaller companies often lack extensive resources and may have limited capabilities or rely on outside organizations and expertise.