Why You Don’t Want to Make Death-Star-Sized Drugs

I was just talking about greasy compounds the other day, and reasons to avoid them. Right on cue, there’s a review article in Expert Opinion in Drug Discovery on lipophilicity. It has some nice data in it, and I wanted to share a bit of it here. It’s worth noting that you can make your compounds too polar, as well as too greasy. Check these out – the med-chem readers will find them interesting, and who knows, others might, too:


So, what are these graphs? They show how well compound cross the membranes of Caco-2 cells, a standard assay for permeability. These cells (derived from human colon tissue) have various active-transport pumps going (in both directions), and you can grow them in a monolayer, expose one side to a solution of drug substance, and see how much compound appears on the other side and how quickly. (Of course, good old passive diffusion is also operating, too – a lot of compounds cross membranes by just soaked on through them).
Now, I have problems with extrapolating Caco-2 data too vigorously to the real world – if you have five drug candidates from the same series and want to rank order them, I’d suggest getting real animal data rather than rely on the cell assay. The array of active transport systems (and their intrinsic activity) may well not match up closely enough to help you – as usual, cultured cell lines don’t necessarily match reality. But as a broad measure of whether a large set of compounds has a reasonable chance of getting through cell membranes, the assay’s not so bad.
First, we have a bunch of compounds with molecular weights between 350 and 400 (a very desirable space to occupy). The Y axis is the partitioning between the two sides of the cells, and X axis is LogD, a standard measure of compound greasiness. That thin blue line is the cutoff for 100 nanomoles/sec of compound transport, so the green compounds above it travel across the membrane well, and the red ones below it don’t cross so readily. You’ll note that as you go to the left (more and more polar, as measured by logD), the proportion of green compounds gets smaller and smaller. They’re rather hang out in the water than dive through any cell membranes, thanks.
So if you want a 50% chance of hitting that 100 nm/sec transport level, then you don’t want to go much more polar than a LogD of 2. But that’s for compounds in the 350-400 weight range – how about the big heavyweights? Those are shown in the second graph, for compounds greater than 500. Note that the distribution has scrunched disturbingly. Now almost everything is lousy, and if you want that 50% chance of good penetration, you’re going to have to get up to a logD of at least 4.5.
That’s not too good, because you’re always fighting a two-front war here. If you make your compounds that greasy (or more) to try to improve their membrane-crossing behavior, you’re opening yourself up (as I said the other day) to more metabolic clearance and more nonspecific tox, as your sticky compounds glop onto all sorts of things in vivo. (They’ll be fun to formulate, too). Meanwhile, if you dip down too far into that really-polar left-hand side, crossing your fingers for membrane crossing, you can slide into the land of renal clearance, as the kidneys vacuum out your water-soluble wonder drug and give your customers very expensive urine.
But in general, you have more room to maneuver in the lower molecular weight range. The humungous compounds tend to not get through membranes at reasonable LogD values. And if you try to fix that by moving to higher LogD, they tend to get chewed up or do unexpectedly nasty things in tox. Stay low and stay happy.