Here’s another solid pharmacokinetics paper, this one from Genentech, with advice on how to extend drug half-life (compare this other recent one). They’re specifically addressing the “make it less lipophilic” rule of thumb that many medicinal chemists have, and they demonstrate that this isn’t exactly a universal law. You have to take it case by case, unfortunately.
They’re working from Genentech’s large database of rat i.v. PK data, stability in rat heptatocytes, and measured (not calculated) logD values. That’s a lot of hard-won data (4767 compounds total), and I’m glad that they’re sharing conclusion from it. The plot at right is an example; each dot is a compound, and they’re shaded according to logD values (<0 to >4). What you see is that IV clearance and (unbound, steady-state) volume of distribution are strongly correlated, and that for the most part this graph is spread along compound lipophilicity. There are outliers (there are always outliers), but that’s the way to bet. As for half-life itself, the spreads in the data are pretty wide, but if anything, higher lipophilicity is correlated with longer i.v. half-life. The Merck paper linked to above also noted that increasing lipophilicity can be a way to extend half-life.
As in that paper, the Genentech team also did an extensive matched-molecular-pairs analysis, and they found a number of transformations that have a good probability of extending half-life (and they’re similar to the earlier paper). Nitrile to fluoroalkyl, methyl to fluorinated methyl, H to CF3, and tetrahydropyran to phenyl all have a good shot. In general, improving clearance in the rat hepatocyte assay has about a 67% chance of helping your half-life, and if you can do that without decreasing lipophilicity, you have an 82% shot. (I would guess that many of those are fluorinations and chlorinations). Just lowering the LogD, on the other hand, only works about 30% of the time.
“But wait”, you may be saying. “If I start halogenating my compound, its solubility will probably go to pieces and its off-target binding may well go up!” This, in those deal-with-the-devil stories, is the point where the mysterious stranger slips up and his business partner catches a glimpse of his cloven feet. That is exactly the sort of deal being offered by pharmacokinetics and compound property analysis: no free lunch has yet been delivered. You have to make these changes in full knowledge that helping one aspect of the compound’s behavior may well hurt another one, and proceed accordingly.
This analysis (as the paper notes) doesn’t deal with charged compounds; they’re a whole other subject. And it also doesn’t go into the other ways around these problems, such as slow-release formulations, etc. But discovery-phase projects generally aren’t thinking about those things either – they’re trying to get compound behavior that doesn’t need the extra work later on. So if you’re in that part of the business, the advice from this paper is to pay attention to hepatocyte clearance assays, don’t be afraid to keep your lipophilicity where it is (or even raise it a bit, while watching for potential trouble), and don’t assume that just making the compound more polar is going to fix much of anything. And pay attention to metabolic hot spots – those are a big reason why those halogenations keep working in these analyses. It’s more work to do metabolite ID, and often more difficult, chemically, to address those problems than it is to make general polarity changes. But it’s time well spent.