In every drug development project, there are put-up-or-shut-up moments. Those are referred to by more traditional project planners as "milestones," but everyone knows what they really are: the times when you walk across the fraying rope bridge, looking nervously at the depths below.
A key moment is when your team has finally made some real advances on the chemical leads you started the project with. When you finally have more potent compounds, with better (and longer-lasting) blood levels, it's time to see if they're more effective in the animals.
They had better be. Because if they aren't, you're going to have some explaining to do. If making the compounds more active and getting more of them into the body doesn't help them, then what are you going to fix now? It's hard to go to the powers that be and say "Well, we're just going to make some more different compounds and. . .well. . .sort of, y'know, hope for the best."
Not that that's not the best course, sometimes. It can be impossible to know why a particular drug bombs out (although you should make every effort to find the reason.) If you're on a good target, or the mood is forgiving, you can make the case that a different drug structure might avoid the whatever-it-was that made the last one a failure.
But without some believable theory, that strategy only works for a while. At some point, the compounds have to show that they're good, and the biological rationale has to show that it's good. If you can't point to some other problem (bad animal model? wrong species?) then you'd better be ready to fold up the tent.
Maybe some new data will show up eventually that sheds some light on why things didn't work; maybe it'll always just be one of those mysteries. The point is, no one on a drug project can allow themselves to get too attached. There's always another one to work on, and they certainly don't all work.