The Rule of 5: Riding the wake

As noted in a previous post, Ro5 is based on analysis of property distributions for a selected set of orally-dosed drugs and the analogous distributions for compounds that were not orally dosed drugs were not examined. Defining a relevant set of compounds that are not orally-dosed drugs requires some thought because there are number of reasons (e.g. lack of biological activity, better compounds in series, binding to anti-target, invalidation of target, portfolio changes, patent scoop, conservative leadership, internal politics...) why a compound might fail to gain membership of this exclusive club. In this post we feature some publications that follow in Ro5's wake.

Six years after Ro5's entrance on the Pharma stage, 'A Comparison of Physicochemical Profiles of Development and Marketed Oral Drugs' appeared in the literature (J. Med. Chem. 2003, 46, 1250-1256). This is an important publication because it fills gaps left by the Ro5 study, in particular the lack of comparison of orally-dosed drugs with a relevant set of other compounds. In this analysis, orally-dosed drugs are defined by 594 marketed oral drugs from the 1999 Physicians' Desk Reference and property distributions are compared with those for compounds at various stages of the development process (e.g. phase 1, discontinued phase 1...).

A number of significant trends are observed, including a steady decrease in molecular weight progessing thru the development process, and fewer rotatable bonds in marketed oral drugs than in compounds earlier in development. On the subject of rotatable bond count, the authors do note that this quantity correlates with molecular weight and we will return to this theme in a future post. An interesting comparsion (see Table 3 in article) is made between the 90% cutoffs for marketed oral drugs and the USAN library used to derive Ro5. Typically each value below which 90% of the data set lies is lower for marketed oral drugs (MW: 473, H-bond donors: 4, H-bond acceptors: 7) with the exception of logP for which different prediction algorithms were used in the two studies. This paper provides original insight while succesfully building on what has come before; it is well worth reading.

Significant trends are necessary but not sufficient to establish a cause and effect relationship. The early development compounds of today are the launched drugs of tomorrow. Could it be that drug molecules are just getting bigger as the low-hanging fruit have already been picked? The authors of 'Characteristic Physical Properties and Structural Fragments of Marketed Oral Drugs' (J. Med Chem. 2004, 47, 224-232) assert that average molecular properties of drugs do not change significantly with respect to when the drugs were launched. However it is noted in 'Time-Related Differences in the Physical Property Profiles' (J. Med. Chem. 2004, 47, 6338-6348) that oral drugs approved for each of the years from 1983 to 2002 have larger median molecular weights than those approved in 1982 and earlier years. Mean values of molecular weight, (O+N), hydrogen bond acceptors, rotatable bonds and rings were significantly higher for oral drugs launched in 1983 through 2002 than for pre-1983 drugs. Neither of these two papers suggests that the more recently launched drugs are more lipophilic.

We discussed effects of correlations beween properties in the previous Ro5 post and it is interesting to see how these are treated. Correlations between 12 properties are shown in Table 2 of JMC47:224, noting that these can be narrowed down to 8 representative properties on the basis of a correlation threshold of R=0.9. A rather unusual approach to examining correlations is used in JMC47:6338 where the authors derive a regression equation for ClogP with molecular weight, (O+N) and (OH + NH) as the X-variables. We would have thought that principal component analysis would have been the tool of choice here and were left wondering why the chosen paths had been taken.

We are simple folk and are left a bit confused by all of this. The pre-1983 drugs do appear to be smaller than those launched at a later date. Was this because of a steady increase with time before 1983 or an initial sharp rise to a plateau that may have been reached 40 years ago? No temporal connection is demonstrated between changes in properties of launched drugs and changes in those properties progessing thru development. Is 1982 the most appropriate point to make the cut, does it matter whether launched drugs are getting bigger and should we even care? We are also confused by the absence of a description of ionisation in these analyses (and indeed in the original Ro5 analysis) since this property is likely to be orthogonal to the (correlated) descriptors that are used. We suggest that ionisation may also occasonally have a modest effect on physical properties and hope that our readers (and the owners of the auto da fe) do not find this view too sacrilegeous.

In the next post on this topic we will take a look at Ro5's little sister. Her name is Ro3.

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