The utilization of spirocyclic scaffolds in novel drug discovery
Spirocycles are ring systems in which two rings are fused through a single atom, referred to as the spiro atom. The ethylene glycol ketal of cyclohexanone is an example of a well known type of spirocycle that is familiar to all organic chemists. Spirocyclic drug molecules have been known for over 50 years [1] In this editorial, we discuss why spirocycles are attractive synthetic targets in drug discovery projects and why we believe they will enjoy increasing attention in future. In support of our argument, we present recent prominent examples of spirocyclic molecules that have appeared in the medicinal chemistry literature and, in some cases, have been successfully developed as drugs. Spirocycles have been employed both as core structures and appended to the periphery of molecules in drug discovery. The major advantage that spirocycles offer as core structures is their inherent three dimensional nature and concomitant ability to project functionality in all three dimensions [2] Significant interactions of a ligand with three dimensional binding site can be achieved more easily using a spirocyclic core than with largely planar (hetero)aromatic systems. Spirocycles are well represented among natural products, molecules which have evolved largely to interact with proteins. The spirocyclic natural product griseofulvin has in fact been used clinically [3] For structure based drug design (SBDD) it is important to note that spirocycles composed of six membered or smaller rings are either rigid or have a limited number of well defined conformations. Many early examples of drugs incorporating spirocycles, e.g. spiperone, and fluspirilene, did not add stereocenters to the molecule. However, to take full advantage of spirocycles, the ability to control stereochemistry at multiple positions on spirocycles of interest is required. Spirocycles have been considered difficult to synthesize due to the presence of a quaternary carbon. The need to control multiple stereocenters further raises the bar on the synthetic chemistry that must be reduced to practice. The substantial number of articles in organic chemistry journals describing syntheses of spirocycles suggests that these challenges are being addressed. In addition to their attractiveness in SBDD, spirocyclic cores have also been utilized in the development of screening libraries and in diversity oriented synthesis [4] Additional rings have also been fused in a spiro fashion to the periphery of molecules of interest, and spirocycles have been appended to molecules of interest to modulate properties such as water solubility, log P, and metabolic stability. Water solubility is an important property for drugs. Generally, alicyclic ring systems are more water soluble than the corresponding aromatic and heteroaromatic systems [5] The sp character of spirocycles is expected to favor water solubility. We believe that another driver for investigating spirocycles is to access novel compounds in untrammeled patent space where broad generic scope can successfully be claimed. Monocyclic ring systems have been extensively investigated; however, as has been pointed out for fused ring systems in general [6] combination of two (or more) monocyclic ring systems provides a multiplicity of spirocycles, many of which have not been synthesized let alone tested for biological activity. A body of work from the Carreira group describing the synthesis of spirocycles incorporating four membered rings illustrates this point [2]
Expert opinion on drug discovery