Here’s a topic that came up in my Twitter feed the other day – I fear it’s unanswerable, but I’d like to hear what people have to say about it. Drug discovery projects start, of course, from a selection of possible chemical matter and chemical series, and they eventually narrow down to a clinical candidate. Various possibilities are given an airing along the way, but the one that makes it through has to come reasonably close to satisfying a whole list of criteria – potency, selectivity, metabolic stability, toxicology, ease of formulation, and others. Some of these can be rather closely coupled, while others are unrelated to each other, and others may be actually opposed (for example, the structural changes that bring on more potency might be just the ones that lead to worse pharmacokinetics).
One question is, though, how many other compounds that would be “development-worthy” are still in there when the project finishes up? That could include ones that were made near the end and didn’t get a full hearing, but I think the question is more directed at analogs that never got made at all. I would guess that most projects could in theory be squeezed for another clinical candidate from their same chemical series – many times this might come from something that is more difficult to make at the bench and was thus not followed.
This is related to a question that’s come up around here before: if you took the same new drug target and set several organizations to working on it at the same time, with their own chemical screens and their own set of medicinal chemists, how many different chemotypes would result? That experiment has been done, quite a few times, under natural conditions, by companies working on the same target but not knowing what the competition was up to. (Coming at a target when you know something about the competing chemical matter is a different case – you’re deliberately trying to avoid the competing patent claims, and you’ll have made some of the other stuff as a comparison for your assays). But in the flying-blind situation, it seems to depend on what sort of SAR the target protein will tolerate. There are cases (such as the PPARs) where the binding pocket accommodates all sorts of stuff and a wide variety of chemical matter shows up, and others where things are so constrained that some common features are almost inevitable. There may be a narrow tunnel in the binding site, or a metal atom that you pretty much have to coordinate to, or a basic region that any potent compound is going to have an acidic group to match with, and so on,
The specific question that came up on Twitter, though, is an even higher bar: how many existing drugs have even *better* variations that just didn’t get pursued? I suppose an alternate way of asking this would be, if you could completely set aside worries about patent claims, how many existing drugs could be re-worked by varying their existing structures to find something better? That immediately suggests the follow-up question of “What do you mean by better?”, and that’s going to be different for different drugs. Could be better selectivity, longer half-life, more (or perhaps less!) potency, avoiding some specific metabolite, etc. There are some drugs that you look at and say “Actually, that one doesn’t really have so many problems”, but there are plenty of others that could in theory be tweaked to something a bit better.
I think the closest thing we have to a real-world example of this is the first wave of deuterated drug analogs. The idea there was that compounds whose biggest problem was metabolism (short half-life or a metabolite best avoided) could be improved by selective deuteration to slow down specific enzymatic bond-breaking events. And at the time, no one wrote their patent language to accommodate such deuterated analogs, so IP-wise the field was pretty open. That story continues: Teva got the first approval in 2017 for a deuterated version of an older compound. Concert Pharmaceuticals is a major player in that area, and they just announced clinical results the other day for a deuterated version of Incyte’s ruxolitinib. So the idea works, but at the same time it hasn’t revolutionized the drug industry, either.
And that’s my guess about the answer to the “better variations” question. I think that clinical candidates (and especially marketed compounds) are certainly at the far end of the big distribution, and that most improvements would probably be small. If a major liability is uncovered, that almost always happens in time for a program to either be killed or to reset and search for newer, better chemical matter. So what makes it out the far end is already pretty good – I think it’s unlikely that there are too many notably better compounds (for the same target) to be made by variations on known drug structures. Thoughts?