Medicinal chemists spend an awful lot of time working with SAR, structure-activity relationship(s). That's how we think: hmm, what happens if I put a chloro there? If I make that ring one size larger? If I flip that stereocenter/add a nitrogen/tie back that chain? Ideally, you pick up on a trend that you can exploit to give you a better compound, but the problem is, no SAR trend lasts forever. Methyl's good, ethyl's fine, anything bigger falls off the cliff - that sort of thing.
Activity "cliffs" of this sort are the subject of a paper earlier this year in the Journal of Chemical Information and Modeling. (For some earlier approaches to this same type of question, see here, here, here, and especially here).This group (from Germany) looked over several public SAR databases and used a new algorithm to extract "matched molecular pairs", which are compounds that differ only at one point in their structure. And what they were looking for wasn't the orderly progressions; they were after the changes that tended to suddenly change the activity of a compound by at least 100-fold. Were there, they wondered, functional group shifts that have a greater or lesser chance of doing that, over a wide range of targets and compound classes?
It looks like there are, and they're the transformations that you might well imagine. Messing around with a carboxyl group, for example, seems rarely to be a neutral event. Carboxylates are so relentlessly polar and hydrogen-bonding that your SAR is probably going to love 'em or hate 'em. The next two liveliest groups were carbonyls (in general) and amines. Of less interest (but equally believable) is the transformation from methyl to bulky alkyl (or vice versa, which is the direction I'd recommend people try to go if at all possible - other things being equal, no one should grease up their compounds unless there's absolutely no choice).
Well, it needs no ghost come from the grave to tell us this, either. How about any surprises? Adding a secondary hydroxyl group was surprisingly silent, compared to what you might picture. And switching from secondary to tertiary amines (just with methyl groups) is a much less conservative switch than you might imagine, with several huge activity shifts across different target classes. Introduction of methyl ethers rarely affected things much one way or another, and that might account for the low tendency of dimethylamine-to-morpholine doing anything. Small halogens on aryl rings (fluorine, chlorine) had low potential to cause big shifts, with ortho-chloros showing no examples of that happening at all. Oddly (at least to me) was the fact that morpholine-to-alkylpiperazine showed almost no big changes, either.
But it has to be emphasized that these are (1) averages and (2) averages over a large (but not gigantic) data set. For example, one of the "no changes at all" transformations is a favorite med-chem isostere, thiophene for phenyl. And that's true - most of the time, that does nothing. But I've seen two examples in my career when that one actually caused a big change in activity, so it's rare, but not impossible. That's the thing that makes med-chem so enjoyable and so frustrating at the same time. It's full of things (like actually discovering a drug) that are rare, but not quite impossible.