For those who don't work in the industry, and wonder what goes on behind the closed doors of the research buildings, allow me to give you a fly-on-the-wall view of a typical meeting of a drug discovery project team. There are no huge revelations here, and I'm not going to try to reproduce 45 minutes worth of talk, but I think that my industrial readers will find this to be a pretty accurate depiction:
(Camera view of the inside of a small conference room, with six or eight people seated around a table)
CHEMIST A: OK, is this everyone that's going to show up? We have to stop this thing of starting all the meetings fifteen minutes late. (Slide goes up on screen from laptop). All right, here are the two scaffolds, and here's where we were last time with them. You guys should know that at the last Senior Review Meeting everyone kept asking when we were going to narrow down on just one of these, and I kept having to tell them that we're not ready to do it yet. But they're getting tired of hearing that.
CHEMIST B: Not as tired as we are of them asking the question. But I guess you probably didn't say that? OK, I'll do Scaffold 1; my lab's been working on that one the whole time. (New slide goes up). As usual, these things are potent out the wazoo, but we can't shake that Other Enzyme activity, and none of these compounds have the plasma stability that we want.
Last time we said that we were going to hang a bunch of stuff off the 4-position to try to fix that metabolic problem, but we only got a few of the things made. Every time you try to put anything useful out there, you get this side product, and most of the time you can't separate the stuff, you can just see it in the NMR and maybe on the LC/MS trace.
But we've made these four analogs - the potency isn't getting any better, but it isn't getting any worse, and we've put 'em in for PK. If they work, though, we're going to have to find another way to do this stuff.
CHEMIST C: Why don't you try to put in those groups via (obscure name reaction)?
CHEMIST B: Because (obscure name reaction) doesn't flippin' work on this system - we tried that, too, and all we get back is starting material. At least the route we've got gives us something. Sometimes. Sort of.
CHEMIST A: What are we going to do if those come back from PK with the same short half-life?
CHEMIST B: Well. . .work on something else, I guess, because if the problem is out here in the 4-position, you'd think that these changes would fix it. Unless we suddenly made some other part of the molecule more likely to be metabolized by messing with this end of it. But you can assume stuff like that all day, and it doesn't get you anywhere. Keep thinking like that, and you'll never make anything.
CHEMIST A: OK, we'll wait for the numbers. My group's been doing the second scaffold, so I'll take that one. (New slide goes up). These have always been the most selective compounds we've got against That Other Enzyme, and they have pretty good PK numbers, but we keep trying to get more potency. We made this series of amines, trying to pick up a hydrogen bond out there in the far binding pocket, but. . .well, most of them don't seem to work. They're really soluble, though. Every time we make something that's really soluble, it doesn't bind.
BIOLOGIST A: Yeah, those things were nice. Should have known.
CHEMIST A: The outlier is that third one, the piperazine. That looks like it might be picking up something, so we're going to make another series off of that one. What we really need is the piperazine with this funky group on it, and you're supposed to be able to buy it from insert name of fly-by-night supplier, but I don't want to depend on those guys.
CHEMIST D: So how long are we going to keep beating on these things? Have you guys ever made anything that's below, like, fifty or a hundred nanomolar?
CHEMIST A: Well, that thiophene compound was the best, and that's what got us excited, you know, but none of the other aryls seemed to work as well. So we've still got the three-position to try out there, and I think we've got some intermediates that we can use to get some analogs. I don't want to pull the plug until we've made those. And we need to make that piperazine series that's up there.
CHEMIST D: But last time you didn't want to pull the plug until you'd made these compounds. Does the plug ever actually come out, or not?
CHEMIST A: Well, not yet, partly because, hey, when you get down to it, this is probably the best series we have to work on. Nothing else gives us those plasma levels.
CHEMIST B: But there's only so much that blood levels can do for you if the potency isn't there. Would you put a hundred nanomolar compound into the animal model?
BIOLOGIST B: I hope not, because as you guys know, that model is a pain in the neck to run, and we'd rather not spend three or four weeks on it unless you've got something that you think is going to actually work.
CHEMIST C: What if you try to mimic that right-hand part of the first scaffold with some sort of cyclic amine goes to screen and waves hands like over here? Piperidine, pyrrolidine - would that hit the same part? It looks like there's space in the X-ray structure to get over there.
CHEMIST A: You want to try it?
CHEMIST C: Well. . .OK. I'll take a look, see if we can get something like that. You guys have any of the ester left, or did you burn it all up already?
(camera pulls back out of the conference room)
. . .and that's how it goes. In fact, that's almost exactly how it goes, most of the time. That's science as it's being done.