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

« Roche Stalls For Time | Main | Squinting At The Pictures, The Modern Way »

December 4, 2008

Curse Of the Lost Compounds

Email This Entry

Posted by Derek

There are some groups of compounds that seem to have a curse on them. They show up in drug screening, they have activity that’s often too good to ignore, but hardly anyone can manage to turn one of them into a drug.

Trifluoromethyl ketones are one example of this. They’re classic inhibitors of proteases, especially serine proteases, and of other enzymes that depend on a serine in their active site. That’s because that ketone really isn’t much of a ketone – the fluorines make the carbon rather unhappy when it’s in that state, electron-poor and ready to pick up a nucleophile and go tetrahedral again. Trifluoromethyl ketones are generally seen in their hydrated state, unless you take care to dry them out, and they’ll work an active-site serine OH into their scheme as well. So you end up with a covalent inhibitor, but a reversible one – the activity comes on slowly, and the compound comes off slowly, too. That trick can work with cysteine nucleophiles, and the hydrate form is also known to coordinate with active-site zinc atoms – so it’s no surprise that the enzyme inhibition literature on these things is mighty extensive: proteases, lipases, esterases, deacetylases, the list goes on for a while.

But although several of these have gone into the clinic over the years, I can’t think of one that’s make it all the way to the market (I’d be glad to hear of any that I’ve overlooked). The best guess is that this isn’t the fault of the functional group, but of the targets it’s been applied to. Some of these enzymes just haven’t panned out, so perhaps the trifluoromethyl ketone awaits its day in the sun.

Another group of this sort is the hydroxamic acid. Its strength is its coordination to zinc atoms, so you see it all over the place in the metallaloprotease literature, and in other zinc-y fields like histone deacetylases. And in vitro, it hardly has a peer. I’ve seen list after list in the literature comparing various zinc-binding head groups, and likely as not, the hydroxamic acid sets the standard every time.

But the reason you see those lists is that people are trying to find something that’ll work other than a hydroxamic acid. There are numerous complaints, ranging from “hydroxylamine is explosive on large scale, you know” and “they’re a pain to make reproducibly” through “they have ugly PK in the animal models” all the way up to “they’re toxic” and “how many of them have ever made it through the clinic?”. How much merit each of these have can be debated, but all together they make an unpleasant picture.

In this case, though, I do know of one that’s made it - SAHA (Zolinza, vorinostat). That one came out of a long-term academic project involving Paul Marks at Sloan-Kettering and Ron Breslow's lab at Columbia, and is one of the not-so-numerous examples of drugs that have made it from the university to the marketplace. Merck signed up to do the clinical and regulatory lifting on this one, and it's now marketed for cutaneous T-cell lymphoma.

So it is possible to get a hydroxamic acid through. "Well, yeah," say the voices, "for cancer, sure. Home of the world's only boronic acid-containing drug. Home, if you really want to get down to it, of nitrogen mustards and God knows what else. Cancer." And it's true that the standards are a bit more relaxed there. I wouldn't necessarily want to give someone a hydoxamic acid every day for the rest of their life, true - the things coordinate iron, for one thing, which isn't always good. But there are other fields where short-term therapy makes sense, and we probably haven't seen the last of this functional group, either.

Comments (31) + TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History


1. Jose on December 4, 2008 10:00 AM writes...

C&EN cover story, "Industry Reforms to drive innovation." Shouldn't that read "Industry cuts, draws and quarters staff to drive bottom line?" The ACS is sounding more and more like the ACC everyday.

Permalink to Comment

2. Anonymous on December 4, 2008 10:28 AM writes...

Dear Derek,

Nice topic. How do you see the presence of "P" in drug candidates? Cheers

Permalink to Comment

3. Hap on December 4, 2008 11:07 AM writes...

How exactly does laying people off and sending jobs to smaller companies and overseas constitute "innovation"? Companies have been doing that for a long time. If companies had ways to find better drug candidates and get them to market more quickly (without getting sued to death or having safety issues), they wouldn't have had to lay off people or outsource in the first place, since they would be able to better use the employees that they have and make more money from them than other companies could. (They might also have their pick of the people laid off from other companies as well.) They might outsource anyway, but that would depend on differences in employee capabilities and cost.

The other problem is the inevitable "we don't have enough chemists" commentary. Either recruiting people who have no better choices or encouraging people with promises of a better tomorrow is a rational response to decreased job security and pay and increasing educational requirements. Um, OK?

Permalink to Comment

4. SRC on December 4, 2008 3:41 PM writes...

C&EN is like People for the pocket protector set (i.e., guys like us). Full of feel good fluff and utter nonsense.

The "we don't have enough chemists" bleat particularly irritates me. American students know perfectly well that a career in science entails a lot of hard work for minimal reward, lousy job security, and a career reporting to someone who ultimately reports to someone with a bachelor's degree in marketing.

That's why they generally avoid it like the plague. Only the truly hardcore committed and/or not too bright types (us again!) ignore that reality and go into it anyway.

Permalink to Comment

5. Hap on December 4, 2008 4:13 PM writes...

Are trifluoromethyl ketones likely to stick (at least temporarily) to lots of things, making their pharmacokinetics not so good? I don't figure the fluorines are coming off, but if the compound is smeared all over, dosing is likely to suck.

Permalink to Comment

6. milkshake on December 4, 2008 9:00 PM writes...

One ugly but potency-improving group is benzamidine. Hard to replace, hard to pro-drug. Free amidine in the drug is bad for oral availability.

Permalink to Comment

7. Dr. Bloomquist on December 5, 2008 4:36 AM writes...

Adrafinil comes to my mind, although it does not currently have FDA approval.

Permalink to Comment

8. Harry on December 5, 2008 8:36 AM writes...

C&E News has been taken over by the PC/Environmentalist/Chemical Hysteric set.

There's not a single issue that doesn't hyperventilate over some largely theoretical risk and/or Global Warming. I've largely quit doing anything but skimming through it.

Some of the technology articles remain interesting, but the editorial slant is pretty blatant.

My $0.02, YMMV.

Permalink to Comment

9. milkshake on December 5, 2008 3:18 PM writes...

Adrafinil is a good point - it is an accidental prodrug that rapidly transforms into modafinil in vivo. Maybe thats why the parent hydroxamic acid does not cause much grief.

Permalink to Comment

10. A nonny mouse on December 15, 2008 6:53 AM writes...

Having worked on hydroxamic acids for many years, and back doing so again, it has to be said that the major problem with the "straight" hydroxamic acids (complex acid, simple hydroxylamine) it that they are extremely metabolically unstable; SAHA for instance has a half-life of 1h and bioavailability of 10%. A hydroxamic acid compound, tepoxalin, has been in use for arthritic dogs for several years, but in human trials caused liver problems due to the large doses to get a decent blood level.

As stated above, hydroxamic acids can be used as pro-drugs such as in ibuproxam and bufexamate.

The option with many hydroxamic acids is to make a "reverse" version (complex hydroxylamine, simple acid). Several companies have been looking at these molecules for many years as anti-bacterial agents which have been on trial at very high doses (3g single, 2g/day 14 days). The problem here, was not the compounds, but rapid bacterial resistance. Novartis continues to work in this field.

Other reversed hydroxamic acids in development include anti-malarial compounds with the N-formyl or N-acetyl hydroxamic acids. This switch, however, does not appear to work with HDAC type molecules.

My own efforts in this field some 20 years ago resulted in "reversed" hydroxamic acids with a half-life of >15h at 1mg/kg in humans. The project was dropped, however, after a take-over (as were most of our projects!).

As with your comments above, I have had people state that they are toxic, but with little real evidence (the person saying this also stated that changing to a different group caused the same toxic effect).

Permalink to Comment

11. John Villaflor on November 7, 2013 10:01 PM writes...

not whenever they genuinely dont care about our survival which they dont it may be bullshit but when it does occur it could possibly be somthing like this . NO warning in the least, thats why many of the major governments of your earth are already making underground bunkers which almost certainly want work in any case

Permalink to Comment

12. Right Move on May 13, 2014 7:49 AM writes...

May I simply just say what a comfort to discover an individual who genuinely knows what they are discussing on the web. You actually know how to bring an issue to light and make it important. A lot more people really need to look at this and understand this side of your story. I was surprised you’re not more popular given that you definitely possess the gift.

Permalink to Comment

13. use generic anchor text on May 14, 2014 6:13 AM writes...

I love reading a post that can make people think. Also, many thanks for permitting me to comment!

Permalink to Comment

14. Download facebook videos on May 20, 2014 12:03 AM writes...

May I simply just say what a relief to discover someone who really understands what they are discussing on the internet. You definitely understand how to bring a problem to light and make it important. A lot more people have to check this out and understand this side of your story. It’s surprising you’re not more popular because you definitely have the gift.

Permalink to Comment

15. aircon service on June 11, 2014 6:04 AM writes...

It’s difficult to find educated people about this subject, but you sound like you know what you’re talking about! Thanks

Permalink to Comment

16. escorts in dubai on June 24, 2014 7:21 AM writes...

I couldn’t refrain from commenting. Perfectly written!

Permalink to Comment

17. viral marketing on July 25, 2014 6:01 PM writes...

I’m pretty pleased to discover this site. I want to to thank you for ones time for this particularly fantastic read!! I definitely loved every little bit of it and i also have you bookmarked to see new things in your site.

Permalink to Comment

18. austin dentist on July 25, 2014 6:23 PM writes...

Spot on with this write-up, I seriously believe that this amazing site needs much more attention. I’ll probably be back again to see more, thanks for the information!

Permalink to Comment

19. Philly Wine on July 25, 2014 7:09 PM writes...

Hi there! I could have sworn I’ve been to this web site before but after browsing through a few of the articles I realized it’s new to me. Anyways, I’m definitely pleased I came across it and I’ll be book-marking it and checking back regularly!

Permalink to Comment

20. Philly Wine on July 25, 2014 7:38 PM writes...

Hi! I simply want to give you a huge thumbs up for the great info you have got here on this post. I will be coming back to your web site for more soon.

Permalink to Comment

21. viral marketing on July 25, 2014 9:25 PM writes...

Your style is unique compared to other folks I’ve read stuff from. Thank you for posting when you have the opportunity, Guess I’ll just bookmark this web site.

Permalink to Comment

22. truth about abs review on July 25, 2014 10:26 PM writes...

You’re so interesting! I do not think I’ve truly read through something like that before. So wonderful to find another person with original thoughts on this subject matter. Seriously.. thanks for starting this up. This website is one thing that is required on the web, someone with a bit of originality!

Permalink to Comment

23. bail bonds pasadena on July 25, 2014 11:10 PM writes...

Pretty! This has been a really wonderful post. Many thanks for providing this information.

Permalink to Comment

24. free email hosting on July 26, 2014 12:50 AM writes...

Having read this I believed it was really enlightening. I appreciate you taking the time and energy to put this informative article together. I once again find myself personally spending a significant amount of time both reading and leaving comments. But so what, it was still worthwhile!

Permalink to Comment

25. dentist austin on July 26, 2014 1:07 AM writes...

Good web site you’ve got here.. It’s hard to find excellent writing like yours nowadays. I truly appreciate individuals like you! Take care!!

Permalink to Comment

26. leds on July 26, 2014 2:24 AM writes...

I seriously love your site.. Pleasant colors & theme. Did you develop this amazing site yourself? Please reply back as I’m wanting to create my very own blog and would like to find out where you got this from or just what the theme is called. Appreciate it!

Permalink to Comment

27. Martin Feely M & F Plumbing and Heating on July 29, 2014 12:37 AM writes...

You have made some really good points there. I looked on the net to find out more about the issue and found most people will go along with your views on this website.

Permalink to Comment

28. John Farant on July 29, 2014 3:59 AM writes...

I would like to thank you for the efforts you’ve put in writing this blog. I really hope to see the same high-grade content from you in the future as well. In fact, your creative writing abilities has motivated me to get my very own blog now

Permalink to Comment

29. sexo con menores on July 29, 2014 7:31 AM writes...

I couldn’t refrain from commenting. Exceptionally well written!

Permalink to Comment

30. information on July 29, 2014 9:26 AM writes...

Oh my goodness! Awesome article dude! Thank you, However I am going through issues with your RSS. I don’t know why I cannot subscribe to it. Is there anybody having the same RSS problems? Anybody who knows the solution will you kindly respond? Thanx!!

Permalink to Comment

31. go here on July 29, 2014 2:13 PM writes...

You’re so interesting! I do not think I’ve truly read something like this before. So good to find another person with some unique thoughts on this subject. Really.. many thanks for starting this up. This site is one thing that is required on the web, someone with some originality!

Permalink to Comment


Remember Me?


Email this entry to:

Your email address:

Message (optional):

Targacept Comes Up Empty, Yet Again
Summer Blogging
The Antibiotic Gap: It's All of the Above
Phenotypic Assays in Cancer Drug Discovery
Neratinib Comes Through For Puma
How Many Biopharma Employees Would Rather Be Working Somewhere Else?
The Broad Gets $650 Million For Psychiatric Research
Put Them in Cells and Find Out