Innovations in the design of stereospecific drug molecular structures: Spirocyclic Scaffolds
Product Manager：Nick Wilde
Spirocyclic compounds are not new as an important area of drug research. In recent years, the demand for compounds with high stereospecificity and spatial structure has been increasing, and the introduction of spirocyclic scaffolds has become an innovative strategy in drug design. Spirocyclic compounds not only provide higher Fsp3 values and stronger three-dimensionality, but also influence drug properties by modulating the synthesis steps and the number of stereocenters.
Application of Spirocyclic Compounds
Spirocyclic compounds are the focus of modern drug discovery and their number of publications in medicinal chemistry journals is increasing every year.
Figure 1. Number of publications with the key word “spiro” in medicinal chemistry journals (J. Med. Chem., Eur. J. Med. Chem., ACS Med. Chem. Lett., ChemMedChem, Bioorg. Med. Chem., Bioorg. Med. Chem. Lett., Bioorg. Chem., and MedChemComm).
As early as the 1950s, the first drug containing a spirocyclic scaffold, spironolactone, was used to treat high blood pressure and heart failure. Subsequently, more and more drugs were found to contain spirocyclic groups, such as Apalutamide for prostate cancer and Ubrogepant for migraine. This suggests that the spirocyclic structure has an important relationship with drug activity and selectivity.
Table 1. Approved Drugs Containing a Spirocycle
The information on indication and molecular targets is extracted from DrugBank unless otherwise annotated.
Advantages of Spirocyclic Compounds
Spirocyclic compounds offer several potential advantages over non-spirocyclic compounds.
1. Increased activity and selectivity. The spirocyclic system restricts the conformation of the molecule and allows locking in the desired conformation between the ligand and the target. For example, improved selectivity for adrenergic receptors and efficient inhibition of PARPase.
2. Improved pharmacokinetic properties. Improved metabolic stability of compounds. For example, improved PLK4 inhibitors by introducing a spirocyclic structure by substituting the olefinic bond.
3. Improved physicochemical properties. Increases the rigidity of the molecule, favoring the balance between solubility and fat solubility.
4. Provides protection for intellectual property. Integration of spirocyclic structures can lead to new patent protection as compared to non-spirocyclic compounds.
Design of New Spirocyclic Compounds
Computer-aided design and artificial intelligence play an important role in optimizing spirocyclic compounds. Researchers have developed a variety of algorithms that evaluate the pharmacodynamically relevant parameters of the large number of candidate molecules generated, from which the best compounds are selected.
X-ray crystallography also provides valuable information for the design of spirocyclic compounds. By determining the eutectic structure of the target protein and the ligand, the interaction mode between the ligand and the target can be understood, guiding subsequent structure optimization.
Through structure-based design, researchers have successfully introduced spirocyclic scaffolds into drug molecules, and the efficacy and selectivity of the drugs have been significantly enhanced. For example, after the introduction of spirocyclic molecules into TPH1 inhibitors, the spirocyclic proline-based scaffolds shown in the figure showed the best properties, which resulted in the optimization of the lead compound 191.
Synthesis and Prospects of Spirocyclic Compounds
For known drug compounds, researchers have developed a variety of novel synthetic routes to construct spirocyclic systems. These synthetic methods provide a foundation for the design and optimization of novel drug candidates.
Spirocyclic scaffolds have been widely used as important tools in medicinal chemistry, playing a unique role in enhancing activity and selectivity as well as pharmacokinetic properties. It brings new opportunities for drug research and development. With the development of synthetic chemistry and computational modeling, it is believed that more and more spirocyclic compounds will be developed as targeted drugs in the future.
Reference
Kerstin Hiesinger, Dmitry Dar’in, Ewgenij Proschak, and Mikhail Krasavin. Spirocyclic Scaffolds in Medicinal Chemistry Journal of Medicinal Chemistry 2021 64 (1), 150-183 https://doi.org/10.1021/acs.jmedchem.0c01473