About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
Not Voodoo

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
Realizations in Biostatistics
ChemSpider Blog
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Eye on FDA
Chemical Forums
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa

Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
Gene Expression (I)
Gene Expression (II)
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net

Medical Blogs
DB's Medical Rants
Science-Based Medicine
Respectful Insolence
Diabetes Mine

Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem

Politics / Current Events
Virginia Postrel
Belmont Club
Mickey Kaus

Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Huge But Effective | Main | Chem Coach Carnival: A Few Questions »

October 23, 2012

Improving Half-Life

Email This Entry

Posted by Derek

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.

Comments (16) + TrackBacks (0) | Category: Pharma 101 | Pharmacokinetics


1. PPedroso on October 23, 2012 9:46 AM writes...

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.

Permalink to Comment

2. Hap on October 23, 2012 9:58 AM writes...

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

Permalink to Comment

3. anon on October 23, 2012 10:08 AM writes...

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.

Permalink to Comment

4. anon on October 23, 2012 10:35 AM writes...

oops... that last comment was supposed to be in the "Huge but effective" post.

Huge but effective?


Permalink to Comment

5. Anonymous on October 23, 2012 11:37 AM writes...

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.

Permalink to Comment

6. nitrosonium on October 23, 2012 12:10 PM writes...

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.

Permalink to Comment

7. paperclip on October 23, 2012 2:47 PM writes...

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

Permalink to Comment

8. Jesse on October 23, 2012 3:16 PM writes...

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

Permalink to Comment

9. Canageek on October 23, 2012 5:03 PM writes...

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.

Permalink to Comment

10. looong life on October 23, 2012 6:08 PM writes...

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

Permalink to Comment

11. Morten G on October 24, 2012 2:27 AM writes...

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

Permalink to Comment

12. chris on October 24, 2012 4:11 AM writes...

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

Permalink to Comment

13. Pete on October 24, 2012 7:26 AM writes...

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.

Permalink to Comment

14. Pharmacologyrules on October 24, 2012 8:52 AM writes...

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.

Permalink to Comment

15. anon2 on October 24, 2012 11:00 AM writes...

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.

Permalink to Comment

16. emjeff on October 26, 2012 7:45 AM writes...

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.

Permalink to Comment


Remember Me?


Email this entry to:

Your email address:

Message (optional):

The Last Post
The GSK Layoffs Continue, By Proxy
The Move is Nigh
Another Alzheimer's IPO
Cutbacks at C&E News
Sanofi Pays to Get Back Into Oncology
An Irresponsible Statement About Curing Cancer
Oliver Sacks on Turning Back to Chemistry