I was having one of those "drug-like properties" discussions with colleagues the other day. Admittedly, if you're not in drug discovery yourself, you probably don't have that one very often, but even for us, you'd think that a lot of the issues would be pretty settled by now. Not so.
While everyone broadly agrees that compounds shouldn't be too large or too greasy, where one draws the line is always up for debate. And the arguments gets especially fraught in the earlier stages of a project, when you're still deciding on what chemical series to work on. One point of view (the one I subscribe to) says that almost every time, the medicinal chemistry process is going to make your compound larger and greasier, so you'd better start on the smaller and leaner side to give everyone room to work in. But sometimes, Potency Rules, at least for some people and in some organizations, and there's a lead which might be stretching some definitions but is just too active to ignore. (That way, in my experience, lies heartbreak, but there are people who've made successes out of it).
We've argued these same questions here before, more than once. What I'm wondering today is, what's the least drug-like drug that's made it? It's dangerous to ask that question, in a way, because it gives some people what they see as a free pass to pursue ugly chemical matter - after all, Drug Z made it, so why not this one? (That, to my mind, ignores the ars longa, vita brevis aspect: since there's an extra one-in-a-thousand factor with some compounds, given the long odds already, why would you make them even longer?)
But I think it's still worth asking the question, if we can think of what extenuating circumstances made some of these drugs successful. "Sure, your molecular weight isn't as high as Drug Z, which is on the market, but do you have Drug Z's active transport/distribution profile/PK numbers in mice? If not, just why do you think you're going to be so lucky?"
Antibiotics are surely going to make up some of the top ten candidates - some of those structures are just bizarre. There's a fairly recent oncology drug that I think deserves a mention for its structure, too. Anyone have a weirder example of a marketed drug?
What's still making its way through the clinic can be even stranger-looking. Some of the odder candidates I've seen recently have been for the hepatitis C proteins NS5A and NS5B. Bristol-Myers Squibb has disclosed some eye-openers, such as BMS-790052. (To be fair, that target seems to really like chemical matter like this, and the compound, last I heard, was moving along through the clinic.)
And yesterday, as Carmen Drahl reported from the ACS meeting in San Diego, the company disclosed the structure of BMS-791325, a compound targeting NS5B. That's a pretty big one, too - the series it came from started out reasonably, then became not particularly small, and now seems to have really bulked up, and for the usual reasons - potency and selectivity. But overall, it's a clear example of the sort of "compound bloat" that overtakes projects as they move on.
So, nominations are open for three categories: Ugliest Marketed Drug, Ugliest Current Clinical Candidate, and Ugliest Failed Clinical Candidate. Let's see how bad it gets!