Medicinal chemists spend a lot of time thinking about the relative greasiness of their molecules. Being professional scientists, of course, we have come up with some slightly more quantitative phrases than “relative greasiness”, but that’s definitely the idea. How hydrophilic/hydrophobic a compound is determines not to what extent it will dissolve in water – it can also be a measure of much of its behavior after it’s dosed in a human patient. Note the weasel word “can” in that last sentence though.
“Greasiness” is usually expressed as logP, the ratio of how much compound dissolves in (greasy) n-octanol versus water, and people have been trying to relate experimental or calculated logP values to drug behavior for decades now. There are broad trends, for sure. Over a certain logP value (I’m not going to give a number!) a given compound is more likely to have trouble getting absorbed and distributed throughout the body. There are plenty of potential problems: it’ll stick to proteins and membranes that you don’t want it to, it might start to pile up in fatty tissue, if it’s greasy with an acidic group it might end up going back around in the bile duct, if it’s greasy with a bunch of carbon-hydrogen bonds it’ll get ripped up by metabolizing enzymes that are on the lookout for that sort of thing, and if you batten it down with a bunch of carbon-fluorine bonds instead it might have a long, trailing half-life of month because it doesn’t get metabolized much at all.
There are worries for the “under” side of the scale, too – wildly water-soluble compounds can just sluice straight out the kidneys sometimes, although that’s not a problem that we often have in drug discovery work. No, the usual struggle is to keep your compound from being a ball o’lard, because most of the time we medicinal chemists tend to make things bulkier and less polar the longer we have them in our hands. We fight against these tendencies a lot more than we used to, to the point that logP concerns can actually become overdone. Attempts have been made to directly correlate logP to likelihood of toxicity, etc., and the arguing has been intense (it’s probably too simple a measure to bear that much weight).
Let’s sidestep that stuff, though, and stipulate for the moment that that making your compound greasier for no real gain in some other area is probably a bad move. All this is prelude to a simple but annoying question: can we, as chemists, compare two different but broadly similar structures and say which one is more polar? OK, back up: sure, we’re a self-confident bunch, but can we say it with any hope of being right? I ask this because of this new paper in J. Med. Chem. It compares simple variations of some absolutely classic cyclic amines: the six-membered ones with the one-carbon-bridged bicyclo variants. You will find both of these all over the literature – if I had a dollar for every morpholine, piperidine, or piperazine claimed in a drug patent I’d be writing this from my private island, although that I assumes that I wouldn’t still be asleep. Anyway, the right-hand forms, drawn in both their “flat” and conformational styles, have one more methylene stuck into them. So does that make them less polar?
Well, if you just hang a methyl off of them, it sure does. And if you just add a methylene into a chain, it sure does. But in this case. . .it doesn’t. The measured polarity (as logD, which is logP done at pH 7.4) is greater every time. And this while calculated logP values either predict that the compounds get less polar or only very slightly more. Experimental data for the win (again and again)! The paper is from AstraZeneca, and it does an AstraZeneca-style tour (sorry guys) through all the methyl substitutions, all the one-carbon bridges, all the two-carbon bridges, etc. This is the big one, though, and it’s both a very meaningful change, one that medicinal chemists often want to put into their molecules, and one that both intuition and quick calculation would tell you isn’t there. But it is. The best explanations for this behavior are increased basicity of the nitrogen (which especially shows up in logD values, of course) and an increased in exposed polar functionality due to the conformational change.
The paper ends up recommending that any team putting one of the six-membered heterocycles into their compound series should investigate the one-carbon-bridged versions as a matter of course. I would definitely agree with that, based on the data shown. I would add a few more general recommendations on top of that one, though. (1) Don’t blindly trust calculated property values, because they’re not as accurate as you think they are. The corollary is even more general: (2) never talk yourself out of an easy experimental test of an idea. And (3) be willing to consider that your chemist’s intuition is wrong – make a few things that you think might not work, once in a while. Our brains are not as accurate as we think they are, either.