This one goes out to a very special amide: azetine amide

A quick look in the CCDC confirms the gut feeling you probably already had: because of the strain of a four membered ring, azetidine amides are the less sterically demanding tertiary amides in medicinal chemistry (given that aziridines are off the table for most medchem programmes-with the mind-boggling exception of RMC-9805). So much so that when you look at the torsion on an aromatic group, azetidine amides look more like secondary amides than tertiary amides.

The CCDC-generated polar histograms below depict the torsions found in the CSD (small molecule Xray database) with the numbers of examples found for the different substructures (By the way, if you like these histograms, you can find a lot more here (link)). The hashed red lines are there only as a visual aid to highlight the differences between the 4 plots.

Quick follow-up comments: tertiary amides are never coplanar with the aromatic. Secondary amides are "less" out of plane but not fully in plane - (I believe the number of torsions close to 0/180 is an artefact from the crystal packing). As mentioned, azetidine amides appear closer to secondary than tertiary (although the low number of examples for the azetidine amides precludes any statistical analysis). Pyridine amides reach something really close to planarity (with an Intra Molecular Hydrogen Bond).

So...why does this matter... well, it means that azetidine amides can have a different SAR vs other tertiary amides ... and should be considered in a class of their own in any amide array.

The first example of this comes from the account of Galapagos scientists on their CFTR potentiator program (JMedChem2021). One of their key pharmacophore features was the planarity of the carboxamide and the central pyridine, held together by 2 IMHBs. It turns out that methylating the secondary amide led to a strong drop in potency, presumably linked to the loss of planarity. It is nice to see the azetidine being tolerated, presumably still allowing a sufficient degree of planarity.

The second example comes from Genentech scientists and their quest for selective CDK2 inhibitors (ACSMedChemLett2023). They started the program with an amide exploration off of an azaquinoline scaffold. What they found is that secondary amides were not selective towards ERK2. However, tertiary amides were more selective. As depicted below, the azetidine example loses its selectivity and behaves more like a secondary amide. One possible explanation comes from a difference in the DFG loop residue (Ala in CDK2 -> Cys in ERK2) which can accommodate more bulk/3D volume in that region of the CDK2 pocket.

The team eventually revisited the azetidine amides without the sp2 nitrogen on the core and additional substituents on the azetidine to reach the perfect balance between potency and selectivity.

The third example comes from Japan Tobacco scientists and their journey to selective CSF-1R inhibitor JTTE-952, depicted below (BMCL2019a, BMCL2019b). Although they do not actually share the data for other rings explored, they mention in the text that the azetidine was the preferred ring. Looking at their bioactive conformation, the coplanarity is quite clear. (As a side note, it is nice to see the catechol part acting as a bidentate HBA (Past post))

The picture below is just an illustrations of a few piperidine amide ligands in the PDB to highlight the non-planarity nature of these (the angle depicted is the pyridine/carbonyl torsion). This does not constitute an absolute proof but does illustrate the different behaviour of azetidine amides..

The following example comes from the MEK1 inhibitor literature. Exelixis scientists focused on mitigating the metabolic fate of the ubiquitous hydroxamic esters found on these allosteric inhibitors, while maintaining some level of planarity in the core (ACSMedChemLett2012). The replacement by an azetidine amide turned out to be instrumental for the discovery of XL518.

If you are wondering if the IHMB would have maintained planarity for bulkier amides, here are examples from the PDB with piperidines and pyrrolidines highlighting how the sterics of these groups outweigh the IHMB with the ortho amino (the angle corresponds to the aromatic/carbonyl torsion).

This latest example is particularly interesting because it highlights that azetidine amides might be the sweet spot when you want a certain degree of coplanarity but the extra HBD of secondary amides is killing your efflux....

Finally, an interesting application of the smaller size of the azetidine comes from AZ scientists in their quest for MCT1 blockers with no atropoisomerism liability (JMedChem2007). In an effort to increase the interconversion rate (around both the amide bond and aryl-CO bonds), the team identified the azetidine amide as an interesting lead. As a side note, in the end the team selected an isoxazoliodine amide(AZD3965) -see comment section on this past post Hydroxamic ester post .

Certainly enough to add a few azetidines when you're doing an amide scan!