Here’s an interesting paper that’s just appeared in ACS Med. Chem. Letters. The authors (Todd Wills and Alan Lipkus, both working at Chemical Abstracts) have gone back over drug approvals with an eye to the chemical structures involved (and working at CA certainly gives a person a leg up on doing that!) They’re addressing the broader topic of pharmaceutical innovation by asking how often new drugs also have new structures that have not previously appeared in any approved medication. Update: here are more thoughts from Wills on this at his own site.
This is done at two levels of detail: scaffold and shape. The former is what you get after you prune all the acyclic side chains off of a structure, and the latter is that scaffold after you set all the remaining atoms back to being just plain carbons. Most approved drugs have some sort of ring in them, so you don’t lose too many by these techniques, and the authors identified the set of 1,089 New Molecular Entities (NMEs) that have been approved by the FDA since 1938. And they assigned the structures of these compounds into one of three classes: “Pioneers” are compounds whose shape and scaffold had never been used in an NME before. “Settlers” are those whose general shape had been used, but not the particular scaffold (so it would allow for moving nitrogens around and the like). And “Colonists” are compounds whose shape and scaffold had already been used, and thus differ only in the side chains.
It turns out that Pioneer molecules are in fact over-represented in lists of therapeutically innovative molecules, which is good to know for sure. As a synthetic chemist, that’s what you would like to hear, but it’s good to see it quantified. And Pioneers are followed (eventually) around 20% of the time by roughly similar Settler molecules, and Settler molecules are eventually followed about 20% of the time by similar Colonist ones. Students of med-chem history may be reminded of Sir James Black’s line about how the best way to find a new drug is to start with an old drug! And indeed, Colonist-class drug structures were the most numerous of the three in FDA approvals from about 1970 to the early 2000s, but since then, Pioneer type structures have taken off and established an unprecedented lead. It appears that this is due to two simultaneous factors – the number of Pioneer structures has increased (and has been increasing, in a rough and now accelerating way, ever since sometime in the 1990s), while the number of Colonist structures has been dropping noticeably. (The intermediate category of Settler compounds has been banging along in third place at roughly similar levels the whole time, in case you were wondering).
The last 20 years have seen 248 Pioneer structures approved, and the authors take a closer look at these. In the 2000-2004 period, Big Pharma companies (AbbVie, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, GSK, J&J, Merck, Novartis, Pfizer, Roche, and Sanofi) accounted for 43% of the Pioneer structure drugs approved, but that number has gone down in every subsequent five-year period, and is now at 30%. But that’s not because the Big Pharma numbers are declining per se; it’s more that the ones coming from everywhere outside that set have increased so strongly. The authors speculate that size and scale of an R&D organization might not be as much of an advantage as it used to be when it comes to having the the resources to make really new structures.
That may well be the case, so it’s interesting to speculate about why that is. Perhaps a wider commercial selection of interesting (and previously-not-used-in-drugs) building blocks? You also wonder about the impact of easy-to-run chemical reactions (metal-catalyzed couplings and so on). Those would seem to be best at generating Settlers and Colonists, but it could be that they allow for easier investigation of novel scaffolds as well. But as for where those new scaffolds come from in the first place, commercial supply is the main change I can think of over the last 20 years. Any other theories?