Lead‐Oriented Synthesis: A New Opportunity for Synthetic Chemistry

Abstract

The pharmaceutical industry remains solely reliant on synthetic chemistry methodology to prepare compounds for small-molecule drug discovery programmes. The importance of the physicochemical properties of these molecules in determining their success in drug development is now well understood but we present here data suggesting that much synthetic methodology is unintentionally predisposed to producing molecules with poorer drug-like properties. This bias may have ramifications to the early hit- and lead-finding phases of the drug discovery process when larger numbers of compounds from array techniques are prepared. To address this issue we describe for the first time the concept of lead-oriented synthesis and the opportunity for its adoption to increase the range and quality of molecules used to develop new medicines.

Shaping a Screening File for Maximal Lead Discovery Efficiency and Effectiveness: Elimination of Molecular Redundancy

“…Applying both filters showed a surprising number of compounds picked up by only a single set of the filters. The merging of the Pfizer and Wyeth screening file gave us the opportunity to revisit the existing filter sets, to combine the experiences from both companies, and incorporate also new findings of structural filters from the literature, [40][41][42][43][44][45][46][47][48] in addition to the creation of a small number of new proprietary filters to remove for example, compounds with very low feature content (no heteroatoms and low structural complexity) and compounds with multiple unattractive features, such as several nitro groups. 48 This knowledge integration resulted in the generation of a combined set of around 540 molecular filters, 55 which were applied to eliminate compounds with structural flaws ahead of the redundancy reduction.…”

“…In parallel, surveying the recent literature describing structural filters allowed us to include additional substructure filters. [40][41][42][43][44][45][46][47][48] Overall, around 140 filters were newly created and combined with the existing filter set, resulting in 540 unique substructure queries.…”

A bio-inspired approach to proline-derived 2,4-disubstituted oxazoles

“…Instant JChem was used for the prediction of the physico-chemical properties of the compounds. Conformational restriction provided by the saturated heteroaliphatic ring of 4 and an improved hydrophilicity are valuable features in leadoriented synthesis in medicinal chemistry [27,28]. …”

A modular lead-oriented synthesis of diverse piperazine, 1,4-diazepane and 1,5-diazocane scaffolds

“…1 The molecular properties of clinical candidates [2][3][4][5] -particularly molecular size and lipophilicity 5 are strongly linked to the probability of successful negotiation of the development process. Optimisation almost inevitably leads to increases in both molecular weight and lipophilicity, making it essential to control the properties of lead compounds.…”

“…molecules that would be good starting points for lead optimisation -have recently been articulated. 1 Sourcing large numbers of lead-like small molecules is a major challenge in maintaining large, high quality screening collections. 1 The vast majority of commercially-available screening compounds -as well as compounds reported in the synthetic chemistry literature -do not have lead-like properties.…”