Here are a few more of those questions that come up during drug research. Readers with experience in the industry may have had to deal with these very ones, and will at least recognize them as the sort of head-scratchers that every project has to deal with. Most of them, as usual, have more than one right answer, depending on the circumstances. So. . .
1. You have good compounds as measured in an enzyme or receptor assay in vitro, but they do nothing what's supposed to be the relevant cell assay. Usually, the assumption is that they have trouble getting into the cells. But then you try them into another cell line that's not necessarily supposed to respond to this target, and they suddenly work just fine. Now what?
2. You have limited chemistry manpower on a project. You're all using a common intermediate, so you put some effort into making a big stock of it for everyone to use. But then a patent application publishes that comes uncomfortably close to what you're working on. The next application from those guys might pull the whole chemical series out from under you. How do you deploy your people to deal with this one?
3. Your team is cranking away, making compounds that are more and more potent in the primary assay against your protein target. The new ones are getting more and more selective against the potential side targets, too, so what's not to like? Well, the compounds are also getting bigger and greasier, and their blood levels are getting worse and worse when dosed in the animal models. When do you call a halt?
4. Several lines of evidence are beginning to make you think that your compounds are doing the right things for the wrong reasons. You're getting the effects you want in vivo, but your initial assays don't correlate with the animal data (or with each other) very well. Do you care, and if so, how much?
5. Your project is narrowing down to two potential candidates. The first one has fair to mediocre potency and selectivity in the assays, but wonderful blood levels. The second is as potent and selective as all get out, but has marginal blood levels and requires ugly dosing vehicles. Which one do you pick, and how do you decide between them?