A recent discussion with colleagues turned around the question: "Would you rather succeed ugly or fail gracefully?" In drug discovery terms, that could be rephrased "Would you rather get a compound through the clinic after wrestling with a marginal structure, worrying about tox, having to fix the formulation three times, and so on, or would you rather work on something that everyone agrees is a solid target, with good chemical matter, SAR that makes sense, leading to a potent, selective, clean compound that dies anyway in Phase II?"
I vote for option number one, if those are my choices. But here's the question at the heart of a lot of the debates about preclinical criteria: do more programs like that die, or do more programs like option number two die? I tend to think that way back early in the process, when you're still picking leads, that you're better off with non-ugly chemical matter. We're only going to make it bigger and greasier, so start with as pretty a molecule as you can. But as things go on, and as you get closer to the clinic, you have to face up to the fact that no matter how you got there, no one really knows what's going to happen once you're in humans. You don't really know if your mechanism is correct (Phase II), and you sure don't know if you're going to see some sort of funny tox or long-term effect (Phase III). The chances of those are still higher if your compound is exceptionally greasy, so I think that everyone can agree that (other things being equal) you're better off with a lower logP. But what else can you trust? Not much.
The important thing is getting into the clinic, because that's where all the big questions are answered. And it's also where the big money is spent, so you have to be careful, on the other side of the equation, and not just shove all kinds of things into humans. You're going to run out of time and cash, most likely, before something works. But if you kill everything off before it gets that far, you're going to run out of both of those, too, for sure. You're going to have to take some shots at some point, and those will probably be with compounds that are less than ideal. A drug is a biologically active chemical compound that has things wrong with it.
There's another component to that "fail gracefully" idea, though, and it's a less honorable one. In a large organization, it can be to a person's advantage to make sure that everything's being done in the approved way, even if that leads off the cliff eventually. At least that way you can't be blamed, right? So you might not think that an inhibitor of Target X is such a great idea, but the committee that proposes new targets does, so you keep your head down. And you may wonder about the way the SAR is being prosecuted, but the official criteria say that you have to have at least so much potency and at least so much selectivity, so you do what you have to to make the cutoffs. And on it goes. In the end, you deliver a putative clinical candidate that may not have much of a chance at all, but that's not your department, because all the boxes got checked. More to the point, all the boxes were widely seen to be checked. So if it fails, well, it's just one of those things. Everyone did everything right, everyone met the departmental goals: what else can you do?
This gets back to the post the other day on unlikely-looking drug structures. There are a lot of them; I'll put together a gallery soon. But I think it's important to look these things over, and to realize that every one of them is out there on the market. They're on the pharmacy shelves because someone had the nerve to take them into the clinic, because someone was willing to win with an ugly compound. Looking at them, I realize that I would have crossed off billions of dollars just because I didn't feel comfortable with these structures, which makes me wonder if I haven't been overvaluing my opinion in these matters. You can't get a drug on the market without offending someone, and it may be you.