Rings in Clinical Trials and Drugs: Present and Future

Abstract

We present a comprehensive analysis of all ring systems (both heterocyclic and nonheterocyclic) in clinical trial compounds and FDA-approved drugs. We show 67% of small molecules in clinical trials comprise only ring systems found in marketed drugs, which mirrors previously published findings for newly approved drugs. We also show there are approximately 450 000 unique ring systems derived from 2.24 billion molecules currently available in synthesized chemical space, and molecules in clinical trials utilize only 0.1% of this available pool. Moreover, there are fewer ring systems in drugs compared with those in clinical trials, but this is balanced by the drug ring systems being reused more often. Furthermore, systematic changes of up to two atoms on existing drug and clinical trial ring systems give a set of 3902 future clinical trial ring systems, which are predicted to cover approximately 50% of the novel ring systems entering clinical trials.

Figure 1

Summary of predicted size of chemical space and key comparisons. Some images were sourced from third parties: “Stars in universe”, permission given by NASA; “Grains of sand on Earth”, permission given by FreeImages; “FDA Approved Drugs”, permission given by FreeImages; “Miles to Alpha Centauri”, permission given by European Southern Observatory (ESO), Davide De Martin.

Figure 2

Example of rings, ring systems, and frameworks for Chlorthalidone.

Figure 3

Histogram comparisons of ring systems in drugs, clinical trials, and those exclusively in drugs that are not currently in clinical trials for (a) number of rings per ring system, (b) percentage of heteroatoms per ring system, (c) percentage of nitrogens per ring system, (d) percentage of oxygens per ring system, (e) percentage of sulfurs per ring system, and (f) percentage of sp³ centers per ring system.

Figure 4

Summary of molecular ring systems (scaffolds) in drugs, clinical trials, reported/synthesized chemical space, and predicted future clinical trial ring systems.

Figure 5

Average number of vectors used per ring vs number of rings per ring system for sets of molecules from drugs and clinical trials. Error bars are the standard deviation of each distribution.

Figure 6

Network diagram showing how ring systems are connected in (a) all compounds in clinical trials. Color of the node represents the highest phase that each ring system can be found. Key: Phase 1 = blue, Phase 2 = green, Phase 3 = purple; drugs = black. (b) Network diagram depicting ring systems in clinical trials that are commonly found in kinase inhibitors (blue nodes); remaining black nodes are all other ring systems present in clinical trials. Central node of the top left cluster (largest cluster) in each subfigure represents benzene.