Are medicinal chemists simple-minded? Have they forgotten how to synthesize molecules? Have they become lazy? If you think the answers to these questions are a loud No, then why some people think that the current Drug Discovery structures are too simple? Keep reading!

Some months ago I saw an entry in Derek Lowe’s blog, In the Pipeline, that opened my eyes to one of the problems in today’s pharma industry.

The post discussed a paper analyzing the type of chemistry carried out in different companies, projects, patents and so. The authors stated that many of the reactions fell into five or six categories, with one of the most important being… yes, you got it, Suzuki couplings !!!! Well, there were many others (amide formation, reductive amination, and so on). I was naive enough to put in my two cents’ worth. To summarize, I suggested that one of the problems was that the low-hanging fruit metaphor also applied to chemistry, and further stated that maybe we should apply newer chemistry to drug discovery. Fancy chemistry, that is.

I am sure the readers have seen this applied before to the pharma industry. Let’s say that the big boom over the last decades in terms of approved drugs, targets and so, was that many of them were low-hanging fruit: things that were easy (you mean, not really easy, but not so impossible as some things we are trying these days), both in terms of biology and chemistry. Once you have picked up all or most of the low-hanging fruit, what remains is the fruit in the upper part of the tree. That is, things which are not easy in terms of biology, chemistry or whatever. For example, I remember a purchasing manager in charge of procuring libraries complaining ten years ago that she was fed up of seeing libraries being sent by combichem companies, a fashion then, filled with amides. Amides, amides, amides. I suppose the explanation is that amides are easy to prepare.

So what is the result? That you end up preparing the things that you know how to prepare and that are relatively easy to prepare. This is especially important in Drug Discovery, with everybody crying for the metrics, number of products delivered, productivity and so. But for some other blog commenters, well… I had comments like ‘why use fancy chemistry? I am putting a product into clinical with just three synthetic steps’. Well, since this guy cannot retaliate here (I know this is cheating, but I don’t mind, really), I will say that comment is a) simplistic and b) lazy. In fact, I strongly suspect that this lucky medicinal chemist preparing a new drug with only three synthetic steps, can do it because somebody else has done a lot of chemistry before so he can have his fancy scaffold or whatever. I doubt very much that his starting material is so simple, and I imagine that he is not performing biosynthesis, where you feed the microbug with a raw material and receive an incredible molecule with a lot of chiral centers and interesting moieties.

Anyway, even in the case that his product is really simple (a new Ibuprofen or similar), the number of easy targets is falling fast. In the end, there is a limit to the number of things you can do through Suzuki couplings. And simply, we cannot keep thinking in terms of ‘I am selecting this hit for the HL because the chemistry is easy’. We need more challenging chemistry to prepare more challenging products. I do not say that we should apply fancy chemistry just because it is fancy, but because it can give us some very interesting leads. And we need a lot of those.