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Pharma 101

Improving Half-Life

There was a question in the comments from a reader who’s picking up med-chem, and I thought it was worth answering out here. I’ve been meaning to shore up the “Pharma 101” category, and this is a good opportunity. So how, in a case like that compound in the previous post, do you increase a compound’s half-life?
The first thing to do is try to figure out why it’s so short. That’s almost certainly due to the compound being metabolized and excreted – once in a while, you’ll find a compound that quietly partitions into some tissue and hides out, but for the most part, a disappearing compound is getting chewed up and spit out. For one that’s being injected like this, you’d want to look in the blood for metabolites, and in the urine for those and the parent compound, and try to see how much you can account for. No point in checking feces or the bile contents – if this thing were dosed orally, though, you’d definitely not ignore those possibilities.
Looking for metabolites is something of a black art. There are plenty of standard things to check, like the addition of multiples of 16 (for oxidations). Examination of the structure can give you clues as well. I’d consider what pieces I’d see after cleavage of each of those amide bonds, for example, and look for those (and their oxidation products). The bromine and iodine will help you track things down in the mass spec, for sure. That phenol over on the right-hand side is a candidate for glucuronidation (or some other secondary metabolite), either of the parent or some piece thereof, so you’d want to look for those. Same thing could happen to some of the free acids after cleavage of the amides. And I have no idea what that difluorophosphonate does, but I’d be rooting through the PK literature to find out what such things have done in the past.
If you can establish some major metabolic routes, then you can think about hardening the structure. What if some of those amides are N-methylated, for example? Can you do that without killing the binding? Would putting another atom on the other side of the phenol affect its conjugation? There are all sorts of tricks, mostly involving steric hindrance and/or changing electron density around some hot spot.
Update: a commenter notes that I’ve left out prodrugs, and that’s quite right. A prodrug is a sort of deliberate metabolism. You put in a group that gets slowly cleaved off, liberating the active compound – esters are a favorite strategy of this sort. Much of the time, a prodrug is put on to improve the solubility and/or absorption of a compound (that is, something polar and soluble grafted onto a brick), but they can certainly influence half-life, too.
The other major strategy is formulation. If you really can’t shore up your structure, or if that isn’t enough, then you can think about some formulation that’ll deliver your compound differently. Would some sort of slow-release help? These things are trickier with injectables than they are with oral medications, from what experience I’ve had, but there are still things that can be done.
So that’s a short answer – there are, of course, a lot of details involved, and a lot of tricks that have been developed over the years. But that’s one way to start.

16 comments on “Improving Half-Life”

  1. PPedroso says:

    Which just proves that experience, at least in the Drug Discovery Biz, counts a lot.
    I mean, you cannot learn these tricks just from reading books or paying attention in your college classes.
    Nice post Derek. Thank you.

  2. Hap says:

    So how is the outsourcing/layoff thing going to help find drugs again?

  3. anon says:

    It’s not a pretty structure, but you have to consider the target, as you correctly point out.
    I remember following up on hits from a PTP1B uHTS effort. We found tons and tons of false positives. Others have reported the same, since phosphatases love to latch onto trace metal contaminants.
    That aryl-CF2-PO3H piece is your tyrosine phosphate mimicking fragment, with one of the fluorines possibly doing n-pi stacking with an aromatic side chain in the protein, and the rest is lipophilicity to give the potency/selectivity you need.
    It’s a decent tool to find out whether that phosphatase is a decent target, so good work IMO.

  4. anon says:

    oops… that last comment was supposed to be in the “Huge but effective” post.
    Huge but effective?

  5. Anonymous says:

    You forgot prodrug. Some prodrugs deliver the drug slowly and some fast, depending on what you’re going for. Think peylation of that beast from the last post.

  6. nitrosonium says:

    Thanks! that really helped me out. i have sooooo much to learn about med chem i am finding this out on a daily basis but every little bit help me develop better relationships with customers over in the med center.

  7. paperclip says:

    @1 wrote everything I was going to write, so I’ll just add thanks and looking forward to more!

  8. Jesse says:

    Working on metabolites may be another approach, as long as the metabolites have similar efficacy. Terfenadine/fexofenadine is one example I can think of.

  9. Canageek says:

    Ok, as someone who did a work term in a nuclear lab, that title was confusing. I imagine it gets even more so when you deal with nuclear medicine, always having to remember which half-life you are talking about.

  10. looong life says:

    Imagine the half lives of these things the US govt are looking for… Nanostructured Active Therapeutic Vehicles (NATV)

  11. Morten G says:

    How about replacing some of the C=O in the amides with C-F?

  12. chris says:

    Also remember that it is duration of action that is often critical, so look for mismatches between PK and PD.

  13. Pete says:

    N-methylation of (acyclic secondary) amides is likely to improve aqueous solubility. Assembling SAR is part of design and it is useful know which (or both or either) of the amide’s HB donor and acceptor are required for binding.

  14. Pharmacologyrules says:

    Technically speaking, a prodrug does not change the t1/2 of the active drug. It can certainly change the kinetics of absorption, and appearance of the active drug in the systemic circulation, but unless the prodrug in and by itself inhibits a clearance mechanism of the active drug, the terminal elimination t1/2 of active drug will not change.

  15. anon2 says:

    Something of a very very basic primer on what can have impact on circculating drug levels, but missing very critical details. What enzyme(s) are rate limiting for metabolic elimination? What drives “distribution” as the primary determinants? Are these passive or active (eg involving transporters)? Are there multiple competing pathways of elimination, so that modification of one will only result in a switch to another, thereby having little overall effect on overall systemic elimnation rate?
    My long, hard earned advise—consult an ADME expert who is well experienced across the board in areas of drug discovery, optimization and development.

  16. emjeff says:

    A nitpick here from a PK guy – the objective should alsways be to decrease clearance. Decreasing clearance will have the effect of increasing half-life, but half-life is a man-made construct. Clearance is the physiological parameter which you want to alter.
    Also, I would point out that formulation can not “increase half-life”. All it can do is slow absorption down.

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