Annual Reports in Medicinal Chemistry: 40

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They suggested that this increase in frameworks was due to the assembly of the same small set of building blocks in novel ways. They further postulated that this could be driven by the adoption of palladium catalyzed couplings such as Suzuki reactions. The properties of rings have been investigated by various groups.

Gibson et al. Ritchie and Macdonald30 explored the impact of aromatic ring count on compound progression and suggested that more than three aromatic rings in a molecule correlated with an increased risk of attrition in development. Young et al. In this study we have extended the work of both enumeration and evaluation of ring space through a historical analysis of rings, ring systems, and frameworks in the U.

The chemical novelty in drugs has been analyzed to assess how many new rings are used per drug and the distribution over time as the rings enter drug space. One of the principal questions addressed in this study concerns innovation versus a pragmatic design strategy within medicinal chemistry and whether this correlates with an increase in success for a drug making it to market. Large macrocycles were considered to be a potentially special case, and we have decided to restrict the maximum single ring size recorded to be less than nine atoms. In silico preparation steps of the drugs included removing salts, standardizing charges at pH 7, and separating the individual components from combination therapies and storing the year of approval.

The exact dates in the FDA Orange Book are only given for drugs introduced after , and so our timeline plots are shown from to , although in certain instances compounds were compared between and and pre There is a possibility that the date of approval could be earlier if we considered registration all over the world; however, we viewed the FDA Orange Book to be the most accurate and well curated data set.

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Figure 2. Terminal groups are non-ring groups that do no connect ring systems. Algorithm Description. The substructure recursive algorithm was implemented in Pipeline Pilot from Accelrys,36 and the ring systems and frameworks were recorded see Figure 2. We did not record the rings as a molecular database in the same way we did for the ring systems and frameworks. We believe breaking the ring bonds can destroy the fundamental core of the ring, and so only the number of rings was recorded for each drug because this is a property often used when analyzing molecular data sets.

However, the exact molecular structures were recorded for the ring systems and frameworks as well as the overall frequency. The cumulative frequency of each ring system and framework was stored as well as the date of approval. When the frequency of ring systems and frameworks was accumulated, all tautomers were enumerated to ensure that the exact structure matching was correct. A ring system is a complete ring or rings formed by removing all terminal and acyclic linking groups without breaking any ring bonds.

Annual Reports in Medicinal Chemistry, Volume 49 - 1st Edition

In the particular case of two rings linked by an acyclic double bond, for example, the serotonin antagonist cyproheptadine, this is also included as a complete ring system and the double bond is not broken. A framework contains all the ring systems but also includes ring systems that are linked by nonterminal acyclic groups. In this analysis a distinction is made between ring systems and frameworks where a ring system can only contain ring bonds including spiro groups and no chain single bonds, although a framework can contain acyclic linking bonds that are nonterminating.

A potential limitation of this approach, if we are simply trying to identify new fragments, is that we do not know whether the activity is due to the rings, the ring systems, the frameworks, the terminal groups, or a combination thereof.

Moreover, potentially important 3D information will be lost when removing terminal aliphatic groups. Furthermore, reactive and unstable compounds could be produced from this analysis because of the computational nature in which the compounds are deconstructed. The mean number of new small molecule drugs, new frameworks, and new ring systems coming onto the market each year is shown in Table 2, along with the standard deviation sd and median values. We also take the view when comparing rings in this analysis that an exact match is the most appropriate for counting the frequency of ring systems and frameworks, although the methodology could be extended to similarity matches.

Furthermore, the core ring systems are often used to describe the lead series within a drug discovery project. We also think this will give an additional level of detail when describing drug space and can be used to benchmark a library. The method can be used to assist the growth of molecular fragments and to answer the question of novelty in a molecular design process.

Table 2. The only noticeable increase from the 22 per year was in and Clearly this could have implications for screening library designs and general medicinal chemistry strategies by considering new chemistry versus chemical coverage. Interestingly the peak in the number of drugs in is mirrored by an increase in the total number of frameworks and ring systems. The initial analysis of the rings in small molecule drugs requires a baseline number for rings, ring systems, and frameworks in current drugs as described in the FDA Orange Book drugs.

By use of the full database of drugs, there are unique frameworks and unique ring systems. The top ring systems are given in Table 1, and these ring systems can be downloaded as an A3 pdf poster along with the frequencies see Supporting Information.

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To achieve this, the total numbers of new drugs, frameworks, and ring systems dx. Total number of drugs compared with drugs containing at least one new ring framework and one new ring system. Figure 5. Percentage of drugs per year containing at least one new framework or ring system. To overcome this issue and to investigate how the new ring systems and frameworks are distributed over time, we have looked at the total number of drugs containing at least one new ring system or framework each year rather than just the overall number of ring systems and frameworks see Figure 4.

The trends for both the ring systems and frameworks seem to match those for the complete drugs, for example, the noticeable peaks in and This could be argued as an increase in frameworks not necessarily resulting in an increase in marketed drugs, which is counter to the observation in Examples of drugs containing more than one new ring system: a etoposide; b lovastatin; c granisetron; d apixaban.

Figure 7. Examples of two drugs launched in the same year with the same new ring system: a topotecan; b irinotecan. From this calculation we can make the following observation: There is no evidence of a correlation between the number of new drugs and the percentage with new ring systems or frameworks. The graphs in Figures 4 and 5 are for drugs containing at least one new ring system or framework.


We could also look at the average number of new rings systems and frameworks per drug; however, it is noted that in fact there are very few drugs that contain more than one new ring system. From an analysis from to which comprises molecules, only 4 drugs have of drugs to normalize for an overall increase in the number of drugs see Figure 5.

From Figure 5 the years and have the highest percentage of drugs containing novel ring systems. These observations could hint at a lack of correlation between ring novelty and the number of drugs successfully making it to market.

Deuterated drug

To statistically quantify this observation, we used the Kendall Tau method as a nonparametric test for statistical dependence. These drugs are the chemotherapeutic etoposide, the cholesterol-lowering drug lovastatin, the antiemetic granisetron hydrochloride, and the anticoagulant apixaban; these could be thought of as the most novel drugs with respect to the ring systems see Figure 6. Again this could have implications on library design, as it is very unlikely that if a new ring system is used, the other rings will also be novel.

This can be restated as 0.

27th Frontiers in Chemistry: Heterocycles and Medicinal Chemistry

Also there has been one example since where two drugs have introduced the same ring system in the same year, namely, the chemotherapeutics topotecan hydrochloride and irinotecan hydrochloride in see Figure 7. Ring Analysis: Ring Replication and Singletons. The next step of the analysis was to assess how the ring systems and frameworks are distributed over time. However, we are more concerned with those ring systems that have been duplicated, so if we consider all nonsingleton ring systems that have been repeated after , i.

Overall there are ring systems. For the remaining ring systems, the time taken for the ring to be repeated has been analyzed. The singletons from the ring systems and frameworks have also been analyzed. There are singleton frameworks out of frameworks, and there are singleton ring systems out of the ring systems. The complete timeline plot is shown in Figure 9, and the 2 years where the number of drugs have peaked and also correspond to the largest numbers of singleton ring systems and frameworks. To further explore this observation, we have focused on the withdrawals of those drugs introduced in Time taken for a ring system to be repeated in a drug.

Another observation is that the numbers of frameworks and ring systems are often independent.

For example, in there are the largest number of frameworks and a relatively low number of ring systems, which implies that this was a year where new frameworks were produced by building up the drugs from known ring systems in a novel way. We have studied the number of new ring systems and frameworks each year and the number of new ring systems and frameworks normalized to the overall number of drugs.

The next area we explored was the calculated properties of ring systems and frameworks. The total number of rings in molecules has been widely studied,16,17,19 and here we show the distribution of the number of rings and ring systems for all drugs see Figure We have also looked at the distribution for the subset of oral drugs data not shown , and the distribution is very similar.

We believe it is more important to look at the rings and ring systems when considering overall numbers, and it is arguably more useful to a medicinal chemist than the number of frameworks. With this in mind the impact of modifying a molecular hit or lead by addition or subtraction of a ring should not be underestimated particularly if the numbers of rings or ring systems are close to these values.

We have attempted to assess whether there has been a slight increase in the mean number of rings and ring systems.

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  6. To see if there is any rise in the size of the drugs, we have also included a box plot for the molecular weight see Figure Leeson et al. Number of singleton frameworks and ring systems per year from to Figure Number of rings and ring systems in drugs. We have also compared the number of ring systems per drug over a longer time frame, i.

    Annual Reports in Medicinal Chemistry

    The size of the ring systems measured by the number of atoms in the ring, excluding exocyclic groups, has also been included. We consider this an interesting observation; however, the mean values for the rings and ring systems over the 2 time periods cannot be distinguished, since they are within 1 standard deviation.

    We have analyzed the number and frequency of a new ring system or framework entering drug space as well as the number and size of rings, but the atomic composition of those dx. Box plot for the number of rings per drug from to showing the median values and upper and lower quartile ranges. The diamonds represent the mean values, and the whiskers represent the standard deviations of the mean. Latest volume All volumes. Search in this book series. Doherty , Mark G. Bock , Manoj C. Desai , John Overington , Jacob J.

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