Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

Abstract

High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability of an innovative, relevant and high-quality compound collection to be screened often dictates the final fate of a drug discovery campaign. Given that the chemical space to be sampled in research programs is practically infinite and sparsely populated, significant efforts and resources need to be invested in the generation and maintenance of a competitive compound collection. The European Lead Factory (ELF) project is addressing this challenge by leveraging the diverse experience and know-how of academic groups and small and medium enterprises (SMEs) engaged in synthetic and/or medicinal chemistry. Here, we describe the novelty, diversity, structural complexity, physicochemical characteristics and overall attractiveness of this first batch of ELF compounds for HTS purposes.

C−H Insertion as a Key Step to Spiro‐Oxetanes, Scaffolds for Drug Discovery

“…The route is based on the selective 1,4-C-H insertion reactions of metallocarbenes, generated from simple carbonyl precursors in flow or batch mode, to give spiro-β-lactones that are rapidly converted into spiro-oxetanes. The three-dimensional and lead like-properties of spiro-oxetanes is illustrated by the conversion of the 1-oxa-7-azaspiro [3,5]nonane scaffold into a range of functionalized derivatives.…”

“…The route is based on the selective 1,4-C-H insertion reactions of metallocarbenes, generated from simple carbonyl precursors in flow or batch mode, to give spiro-β-lactones that are rapidly converted into spiro-oxetanes. The three-dimensional and lead like-properties of spiro-oxetanes is illustrated by the conversion of the 1-oxa-7-azaspiro [3,5]nonane scaffold into a range of functionalized derivatives.Modern drug discovery programs drive an appetite for new, low molecular weight bioactive molecules. In support of the wellestablished drug discovery process, strategies such as diversity-oriented synthesis (DOS), lead-oriented synthesis (LOS), biologyoriented synthesis (BOS), and fragment based drug discovery (FBDD) have recently emerged as tools to accelerate the search for new drug candidates.…”

“…As part of our work under the ELF programme, [4] we were intrigued by the recent interest in spirooxetanes, [5] and identified the little known 1-oxa-7-azaspiro [3,5]nonane ring system (Figure 1) as an ideal scaffold for drug discovery.…”

“…One contemporary initiative, the European Lead Factory (ELF), [3] was established with the precise goal of identifying compound libraries that fulfil the above criteria. As part of our work under the ELF programme, [4] we were intrigued by the recent interest in spirooxetanes, [5] and identified the little known 1-oxa-7-azaspiro [3,5]nonane ring system (Figure 1) as an ideal scaffold for drug discovery.…”

Assessing molecular scaffolds for CNS drug discovery

“…Moreover, the problem of sourcing large numbers of lead-like molecules is heightened when the issue of chemical diversity is also considered. To address these challenges, lead-oriented synthesis has emerged as an approach in which molecular property and diversity analyses inform the development of new synthetic methodology [7][8][9].…”