Spirocycles in Drug Discovery

Medicinal chemists are constantly in search of molecules that explore new chemical space whilst looking for novelty amongst the plethora of patented molecules. Three-dimensionality is also key in maintaining solubility of new drug compounds.

Oxetanes have long been known in medicinal chemistry as very useful bioisosteres or surrogates for carbonyl or gem-dimethyl motifs. They reduce lipophilicity and therefore increase solubility when compared to their gem-dimethyl counterparts and reduce metabolism and are less likely to be covalent binders in comparison with the corresponding carbonyls. They have also been shown to be excellent hydrogen bond acceptors,   Penny 1

Whilst oxetanes have been thoroughly explored in drug discovery as a single motif, their composition in spirocycles has been relatively unexplored. In 2008, Carreira et al compared parent amino heterocycles (eg. azetidines, pyrrolidines and piperidines) with the corresponding spirocycle incorporating oxetanes.

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In all cases, the spirocycles were stable at pH 1-10 and were considerably less basic than their parent compounds due to their conformation. All have lower logD than their gem-dimethyl and carbonyl analogues. In the cases shown above, the spirocycles also exhibited far lower intrinsic clearance than the carbonyl or parent compounds.

Morpholine moieties are also regularly found in drug discovery programs and in final drug candidates, however, the spirocyclic surrogate seems to fall under the radar despite it being much more soluble, less lipophilic and more metabolically stable.

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In addition, the oxygen lone pair is shown to be 1.3 angstroms further out than in morpholine and can therefore be regarded as an elongated morpholine (similar to piperidone but much more metabolically stable). This spirocycle could be used to probe chemical space within a binding site or could in fact have a stronger interaction within the binding site due to probing deeper within a given pocket of the site.                          Penny 4

Carreira et al later looked at the differences between morpholines, piperidines, piperizines and thiomorpholines compared with their spirocylic analogues in terms of their physico and biochemical properties. In general, the spirocyclic compounds had higher solubility, lower logD and were intrinsically more stable in human and liver microsomes compared to the parent compounds.

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The authors proceeded to synthesise the antibacterial compound Ciprofloxacin with the piperazine motif replaced with either a piperizine-like spirocycle (Compound A) or the morpholine-like spirocycle (Compound B). Both compounds showed comparable MIC and most interestingly, neither A nor B showed any sign of metabolism in human microsomes whereas Ciprofloxacin showed slight metabolism.

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Mykhailiuk et al published an interesting paper very recently which is what initially sparked this blog. They comment on the distinct lack of spirocyclic compounds in FDA approved molecules despite the number of patents surrounding such molecules slowly increasing in recent years. The authors describe spirocycles as an “overlooked motif for drug discovery”.  Their work surrounds the replacement of 2-substituted piperidines with 2-azaspiro[3.3]heptane surrogates. These compounds are not synthetically challenging as one might imagine and they originate from commercially available, relatively cheap starting materials with synthesis easily scalable to 50g of product in a single batch. They also demonstrate that the synthesis has scope and can tolerate a wide range of substituents.

The synthesis of the spirocyclic analogue of FDA-approved local anaesthetic Bupivacaine was completed by this group to compare this motif in a drug discovery setting. The results showed that despite their analogue exhibiting slightly higher plasma protein binding and in-vitro metabolism, in-vivo, their analogue showed faster onset and similar duration to Bupivacaine with lower systemic toxicity than the FDA approved drug.                               Penny 7Whilst spirocycles remain unrepresented in FDA approved molecules, it is clear that interest both within academia and industry is growing. With studies like these being published more frequently demonstrating the improved drug-like properties of these compounds when compared to their monocyclic counterparts, it is likely that it won’t be long before these motifs are seen in approved drugs.

Blog written by Penny Turner


Angew. Chem. Int. Ed., 2010, 49: 9052-9067

Angew. Chem. Int. Ed., 2008, 47: 4512-4515

Angew. Chem. Int. Ed., 2010, 49: 3524-3527

Angew. Chem. Int. Ed., 2017, 56: 8665-8869


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