29 March 2021

Fragment chemistry roundup part 5

Last week we highlighted three chemistry-focused papers, and this week we’ve got three more. And to add a third three, all these papers address “three-dimensional” fragments.
The first, in ACS Med. Chem. Lett. by Brian Cox (University of Sussex), Philip Cox (AbbVie) and colleagues, describes using photochemical [2 + 2] cycloadditions to generate bridged pyrrolidine fragments, which can be further diversified.

The researchers analyzed 54 products by principal moments of inertia (PMI) and plane of best fit (PBF), which revealed them to be quite shapely, more so than AbbVie’s Rule of Three collection. Interestingly, amide derivatives with aromatic substituents were often shapelier despite being less saturated, and the researchers thus caution against using Fsp3 as a proxy for shapeliness – a point Teddy made several years ago.
The next paper, open access in ChemComm, also deals with cyclobutane-containing molecules. However, rather than building them from scratch in cycloaddition reactions, David Spring and collaborators at University of Cambridge and California State Polytechnic University Pomona use palladium-catalyzed C-H arylation to functionalize the rings. Lactonization and further derivatization generates a range of molecules.

The researchers generated a virtual library of 90 scaffolds that were rule-of-three compliant and quite shapely. It would be interesting to explore this chemistry on the bridged pyrrolidines of the previous paper – perhaps deliberately “losing control,” as discussed last week.
Finally, in Chem. Eur. J., Peter O’Brien (University of York) and a large group of collaborators from academia and industry describe (also open access) the “design and synthesis of 56 shape diverse 3-D fragments.” Because of their prevalence in drugs, pyrrolidines and piperidines were chosen as targets. The researchers specifically set out to make diverse molecules that would be shapelier (as assessed by PMI) than members of typical libraries. In considering three-dimensionality, the researchers considered not just the lowest energy conformation, as is typically done, but also other conformations with energies up to 1.5 kcal/mol higher; these would be present roughly 8% of the time at 37 °C. Some of the molecules are shown.

A PMI analysis of these fragments revealed them to be more three-dimensional than representatives of six commercial fragment libraries. In fact, although three of the commercial libraries are touted as being “3D,” a PMI analysis revealed them to “have only a marginally better 3-D profile compared to the standard 2-D rich commercial fragment libraries.” As in the paper discussed above, there was no correlation between Fsp3 and PMI.
Despite being relatively simple, 42 of these molecules had been previously unreported. In addition to their shapeliness, they also adhered to the rule of three, with an average ClogP of just 0.54. Moreover, 52 of the fragments were stable for >6 weeks in DMSO, 48 were stable in aqueous buffer for >24 hr, and 40 of them were soluble at >0.5 mM in buffer.
Most of these fragments are available for screening at the Diamond XChem facility. It will be interesting to see what kinds of hit rates they produce, and whether they generate superior leads. As we noted last year, the majority of drugs are not particularly shapely. Still, it is fun to explore new regions of chemical space, and these three papers are good starting points.

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