A unified lead-oriented synthesis of over fifty molecular scaffolds

Abstract

Controlling the properties of lead molecules is critical in drug discovery, but sourcing large numbers of lead-like compounds for screening collections is a major challenge. A unified synthetic approach is described that enabled the synthesis of 52 diverse lead-like molecular scaffolds from a minimal set of 13 precursors. The divergent approach exploited a suite of robust, functional group-tolerant transformations. Crucially, after derivatisation, these scaffolds would target significant lead-like chemical space, and complement commercially-available compounds.

Saturated Heterocyclic Aminosulfonyl Fluorides: New Scaffolds for Protecting‐Group‐Free Synthesis of Sulfonamides

“…1 HNMR, 19 FNMR, and 13 CNMR spectra were recorded at 500 or 400.0, 376, and 101 or 125 MHz, respectively.C hemical shifts are reported in ppm downfield from SiMe 4 ( 1 H, 13 C) or CFCl 3 ( 19 F) as internal standards. All starting materials were provided by Enamine Ltd. and were used without further purification.…”

“…Lead-orienteds ynthesis, coined by Churcher and co-workers, [18] identifiesl ead-like molecular scaffolds with ah igh fraction of sp 3 carbon atoms. [19][20][21] This approach was shown to be effective to control the high quality of compound libraries. Ali- Figure 1.…”

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

“…Indeed, a significant number of unprecedented spiro, bridged, and fused polycycles with different degrees of saturation, conjugation, and substitution have been synthesized and expanded to a library format. This has been recently exemplified by several publications from the ELF chemistry groups detailing the associated design and validation aspects [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. Given that most theoretical ring systems remains unexplored [39], the synthesis of novel rings represents one of the strategies embraced by the ELF chemistry consortium to expand the available chemical space.…”

Assessing molecular scaffolds for CNS drug discovery

“…In order to illustrate our approach and before undertaking any experimental work, we scored a range of related pyrrolidine-based scaffolds that would be potentially accessible using a unified synthetic approach [27]. We proposed 25 potential scaffolds that might be prepared by combining an allylic carbonate building block with variable amine and aryl bromide building blocks (Figure 2, Panel A).…”