13 April 2020

Fragment chemistry roundup part 3

Last week’s post discussed three papers describing new chemistries for building fragment libraries. The theme continues this week with three more.

The first, in ACS Med. Chem. Lett. from Philip Garner (Washington State University Pullman), Philip Cox (AbbVie), and colleagues describes the synthesis of a library of pyrrolidine-based fragments in just three steps. A chiral auxiliary, which is subsequently removed, enables an asymmetric cycloaddition reaction to generate pyrrolidine rings containing three defined stereocenters. Using this method, the researchers made 48 fragments from simple starting materials.

As one might predict looking at the structures, the fragments have low lipophilicity (average AlogP = 0.12) and high levels of saturation (Fsp3 = 0.47), though with an average MW = 225 they are a bit portly.

The fragments are also quite shapely, as assessed both by principal moments of inertia (PMI) or plane of best fit (PBF). The researchers acknowledge that this shapeliness increases the fragments’ molecular complexity, and they also note the difficulty of quantifying this, “as current estimates do not take into consideration 3D, let alone the multidimensional descriptors of chemical space.” Thus, they may have lower hit rates. Hopefully we’ll see screening data from this set at some point in future.

Diversity oriented synthesis (DOS) has only been occasionally applied to fragments, perhaps in part due to issues Teddy raised in his Safran Zunft Challenge. In an (open access) Bioorg. Med. Chem. Lett. paper, Nicola Luise and Paul Wyatt (University of Dundee) describe a set of 22 fragments in 12 scaffolds starting from just 3 precursors; a few examples are shown.

Although the embedded pyrazine, pyridine, and pyrimidine moieties are found in many drugs, some of the bicyclic cores are novel or rarely found in commercial sets.

In both these papers, the chemistry is sufficiently straightforward that a hit could rapidly lead to numerous analogs, which is a selling point for including them in a library. But in advancing other fragments a common problem is that the analog you most want to make is synthetically difficult. A crystal structure may reveal that an otherwise useful synthetic handle is making intimate contacts with the protein, while a hard-to-functionalize aliphatic ring is situated next to an attractive subpocket. A clear example of this is the phase 2 IAP inhibitor ASTX660 from Astex, whose fragment starting point consisted of a piperidine linked to a piperazine.

Perhaps building on this experience, Rachel Grainger, Chris Johnson, and collaborators from Astex, University of Cambridge, and Novartis have published in Chem. Sci. a high-throughput experimentation method to functionalize cyclic amines. The researchers used nanomole-scale reactions run in 1536-well plates to explore and optimize photoredox-mediated cross-dehydrogenative heteroarylation.

After optimizing conditions, the researchers moved to larger (milligram) scale to couple 64 different protected amines against heteroarene 3a and 48 heteroarenes against N-Boc-morpholine, thereby obtaining a variety of interesting molecules, many of which contain polar functionalities. Finally, they used flow chemistry to generate more than a gram of product 5g, demonstrating scalability. The paper ends with a half dozen examples of fragments taken from recent reviews, noting how the cross-dehydrogenative coupling could be used to elaborate them.

Progress often comes from expanded possibilities. By facilitating new chemistries, this paper lowers the barriers for drug hunters to make the most promising molecules. And taken together, all six of these papers advance the field of fragment chemistry.

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