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GlaxoSmithKline (GSK) has previously reported on the development of a GSK solvent guide, the incorporation of lifecycle impact and the expansion of the guide including a customisable version intended for posting in different business areas. This guide has recently been enhanced by: (1) adding 44 additional solvents, many of which have literature claims to be “green”; (2) adjusting the way in which multiple health, environment, safety, and waste categories are combined to reach a single composite score and colour assignment; (3) updating the data behind all scores, especially toxicology and health hazard assessment, and revising the methodology to reflect current guidelines and data. The full methodology behind this work is hereby shared. The new GSK Solvent Sustainability Guide enables GSK scientists to objectively assess solvents. It facilitates both comparison of individual sustainability criteria, and a composite score and colour for rank ordering, incorporating multiple facets of sustainability.

Pharmaceutically important chiral fluorolactam derivatives bearing a fluorine atom at a stereogenic centre were synthesized by a route involving copper catalyzed selective direct fluorination using fluorine gas for the construction of the key C–F bond and a biochemical amidase process for the crucial asymmetric cyclisation stage. A comparison of process green metrics with reported palladium catalyzed enantioselective fluorination methodology shows the fluorination-amidase route to be very efficient and more suitable for scale-up.

A novel pyrrole-2-carboxamide series of p38α inhibitors, discovered through the application of virtual screening, is presented. Following evaluation of activity, selectivity and developability properties of commercially available analogues, a synthesis program enabled rapid assessment of the series’ suitability for further lead optimisation studies.

The identification and progression of a potent and selective series of isoquinoline inhibitors of IκB kinase-β (IKK-β) are described. Hit-generation chemistry based on IKK-β active-site knowledge yielded a weakly potent but tractable chemotype that was rapidly progressed into a series with robust enzyme and cellular activity and significant selectivity over IKK-α.

Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinases, particularly AurA and AurB. A template-hopping strategy was used to identify a series of aminobenzothiazole Itk inhibitors, which utilized an inherently more selective hinge binding motif. Crystallography and modeling were used to rationalize the observed selectivity. Initial exploration of the SAR around this series identified potent Itk inhibitors in both enzyme and cellular assays.

Reagent guides ranking commonly used reagents for 15 transformations have been developed to reduce the environmental impact of drug discovery and development. Reagents have been scored by a combination of health, safety and environmental risk phrases, life cycle analysis (where possible) and an assessment of the chemistry including considerations of atom efficiency, stoichiometry, work-up and other issues. Guides covering alkene reduction, amide formation, C–H bromination, C–H chlorination, deoxychlorination, epoxidation, ester formation, ether formation, fluorination, iodination, ketone reduction, nitro reduction, oxidation of alcohols to aldehydes and ketones, reductive amination and sulfur oxidation are shared, with an explanation of the methodology behind their generation.