Corante

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: derekb.lowe@gmail.com Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
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
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
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
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


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


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
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

« The Ultimate in Personalized Medicine | Main | Virtual Biotech, Like It or Not »

March 26, 2012

What's the Ugliest Drug? Or The Ugliest Drug Candidate?

Email This Entry

Posted by Derek

I was having one of those "drug-like properties" discussions with colleagues the other day. Admittedly, if you're not in drug discovery yourself, you probably don't have that one very often, but even for us, you'd think that a lot of the issues would be pretty settled by now. Not so.

While everyone broadly agrees that compounds shouldn't be too large or too greasy, where one draws the line is always up for debate. And the arguments gets especially fraught in the earlier stages of a project, when you're still deciding on what chemical series to work on. One point of view (the one I subscribe to) says that almost every time, the medicinal chemistry process is going to make your compound larger and greasier, so you'd better start on the smaller and leaner side to give everyone room to work in. But sometimes, Potency Rules, at least for some people and in some organizations, and there's a lead which might be stretching some definitions but is just too active to ignore. (That way, in my experience, lies heartbreak, but there are people who've made successes out of it).

We've argued these same questions here before, more than once. What I'm wondering today is, what's the least drug-like drug that's made it? It's dangerous to ask that question, in a way, because it gives some people what they see as a free pass to pursue ugly chemical matter - after all, Drug Z made it, so why not this one? (That, to my mind, ignores the ars longa, vita brevis aspect: since there's an extra one-in-a-thousand factor with some compounds, given the long odds already, why would you make them even longer?)

But I think it's still worth asking the question, if we can think of what extenuating circumstances made some of these drugs successful. "Sure, your molecular weight isn't as high as Drug Z, which is on the market, but do you have Drug Z's active transport/distribution profile/PK numbers in mice? If not, just why do you think you're going to be so lucky?"

Antibiotics are surely going to make up some of the top ten candidates - some of those structures are just bizarre. There's a fairly recent oncology drug that I think deserves a mention for its structure, too. Anyone have a weirder example of a marketed drug?

What's still making its way through the clinic can be even stranger-looking. Some of the odder candidates I've seen recently have been for the hepatitis C proteins NS5A and NS5B. Bristol-Myers Squibb has disclosed some eye-openers, such as BMS-790052. (To be fair, that target seems to really like chemical matter like this, and the compound, last I heard, was moving along through the clinic.)

And yesterday, as Carmen Drahl reported from the ACS meeting in San Diego, the company disclosed the structure of BMS-791325, a compound targeting NS5B. That's a pretty big one, too - the series it came from started out reasonably, then became not particularly small, and now seems to have really bulked up, and for the usual reasons - potency and selectivity. But overall, it's a clear example of the sort of "compound bloat" that overtakes projects as they move on.

So, nominations are open for three categories: Ugliest Marketed Drug, Ugliest Current Clinical Candidate, and Ugliest Failed Clinical Candidate. Let's see how bad it gets!

Comments (58) + TrackBacks (0) | Category: Drug Development | Drug Industry History


COMMENTS

1. myma on March 26, 2012 8:05 AM writes...

Aliskiren.
Lets throw in some peptide like things on this side, and a big ole floppy chain on the other side.

Permalink to Comment

2. PharmaHeretic on March 26, 2012 8:05 AM writes...

I am sure that you will get some entries about early HIV protease inhibitors and glycopeptide type antibiotics, but why do so many people forget Suramin? It was developed in 1916 and is still used for non-CNS Trypanosoma infections.

http://en.wikipedia.org/wiki/Suramin

Permalink to Comment

3. petros on March 26, 2012 8:18 AM writes...

ebselen is small but not pretty
http://en.wikipedia.org/wiki/Ebselen

and Bortezomib is hardly over appealing

Permalink to Comment

4. Curious Wavefunction on March 26, 2012 8:23 AM writes...

Isn't there usually an injunction against putting biaryls in a drug? But that's probably more so if the biaryl is terminal.

I don't know about ugliest, but the most unlikely drug I have personally ever seen is metformin.

Permalink to Comment

5. Plan B in Progress on March 26, 2012 8:29 AM writes...

Biogen's BG-12 has to be mentioned, as does Novartis' Fingolimod (Gylenia). BG-12 makes me shake my head every time I look at it and fingolimod's definitely in the "how does that not get cleared quickly" category

Permalink to Comment

6. Quintus on March 26, 2012 8:32 AM writes...

@myma: Aliskiren.
There are lots of stories behind that one, which one day I will (may) relate.
Try come up with and alternative synthesis that will deliver >500Kg drug product per batch!

Permalink to Comment

7. jd on March 26, 2012 8:34 AM writes...

Funny. You're worried that this fun little exercise will provide ammo for those who want to (wrongfully, in your mind) pursue un-drug like leads. One the other hand, the longer this little list gets, the less of liability the 'ugliness' seems to be, no? I'll bet if everyone chimed in with their vote, the bias toward compounds that fit neatly into a small, heteroaromatic, supposedly orally bioavailable box would begin to look a bit more like ideology that statistical truth.

Personally, I really don't care for subjective labels on the asthetics of a drug. I've have plenty of people laugh at structures a priori and reject ideas outright based on cursory inspection of a chemical structure. Then they are shown the biology. Then silence. As a chemist, I'm sort of embarrassed by this pattern.

Permalink to Comment

8. Snickers on March 26, 2012 8:35 AM writes...

The fluoromethyl thiol ester of fluticasone (part of Advair) sure looks scary to me.

Permalink to Comment

9. HelicalZz on March 26, 2012 8:53 AM writes...

Depends. What is the drug supposed to do? Does it need to be oral, or is injectable OK? Does it need to hang around in the bloodstream for awhile, a long time, a real long time, or not at all? Is the target (assuming it was designed against one) extracellular, cytoplasmic, nuclear, foreign (such as with antibiotics).

You want ugly, how about every vaccine. And how 'undruglike' are Mabs? Not all drugs are to be taken once a day for the rest of your life, but the industry sure seems pigeonholed into finding the ones that could be.

Zz

Permalink to Comment

10. barry on March 26, 2012 8:53 AM writes...

gonna be hard to beat the mustard gases for "ugly" http://en.wikipedia.org/wiki/History_of_cancer_chemotherapy

Permalink to Comment

11. HelicalZz on March 26, 2012 9:01 AM writes...

Vitamin B-12

http://en.wikipedia.org/wiki/Vitamin_B12

Zz

Permalink to Comment

12. Ben Zene on March 26, 2012 9:03 AM writes...

Have a look at BIIE-0246. Start with arginine and keep bolting bits on until it damn well does something....

Permalink to Comment

13. milkshake on March 26, 2012 9:22 AM writes...

Itraconazole and Montelukast

Permalink to Comment

14. BHip on March 26, 2012 9:24 AM writes...

Re: # 5- I use Fingolimod (Gylenia/FTY720) as an example to chemists (I am a biologist) as not being to hasty in dismissing a drug based on its structure. Not only does it not get cleared quickly, its T1/2 is probably too long for its own good- more like an antibody.

Permalink to Comment

15. CMCguy on March 26, 2012 9:44 AM writes...

Paclitaxel with its dreaded Cremophor formulation would be my selection for Ugliest Marketed Drug. Most of the analogs did not do much to improve physiochemical properties and in cases made worse.

Permalink to Comment

16. Anonymous on March 26, 2012 9:44 AM writes...

eribulin. Multiple fun features.

http://en.wikipedia.org/wiki/Eribulin

Permalink to Comment

17. Anonymous on March 26, 2012 10:00 AM writes...

Alkynes anyone?
http://en.wikipedia.org/wiki/Linagliptin

Permalink to Comment

18. Rick Wobbe on March 26, 2012 10:49 AM writes...

Copaxone. Looks like the product of a broken peptide synthesizer to me.

Permalink to Comment

19. Rick Wobbe on March 26, 2012 10:52 AM writes...

@17 What's wrong with alkynes? You prejudiced against sp hybridization?

Permalink to Comment

20. Giagan on March 26, 2012 10:55 AM writes...

This one's a beaut:
http://en.wikipedia.org/wiki/Eltrombopag

Permalink to Comment

21. Escapee on March 26, 2012 11:18 AM writes...

Well, Retapamulin still makes me laugh: http://en.wikipedia.org/wiki/Retapamulin

Permalink to Comment

22. Josh Bloom on March 26, 2012 11:26 AM writes...

Look up Antabuse (disulfiram). Crazy looking

Permalink to Comment

23. Tocrat on March 26, 2012 11:26 AM writes...

cis-platin yuck

Permalink to Comment

24. Orthogon on March 26, 2012 11:30 AM writes...

A lot of the estrogen receptor antagonists/SERMs are pretty homely (tamoxifen, for instance), but fulvestrant has to take first prize in the estrogen receptor ugly contest. All that grease might explain why it's given intramuscularly once or twice a month.

Wonder which drug has the highest logP value?

Permalink to Comment

25. startup on March 26, 2012 11:32 AM writes...

Salvarsan?

Permalink to Comment

26. Chrispy on March 26, 2012 11:39 AM writes...

I'm with Rick @18 -- copaxone. A semi-defined polymer of four amino acids. Oy vey. With the extra kicker that we don't really know how it works -- it is said to distract the immune system. Or something.

Permalink to Comment

27. DJ DrZ on March 26, 2012 11:49 AM writes...

Love the suramin reference!!! I worked on it as a tool compound at a previous compound and actually published on it as a inhibitor of PPI.

Permalink to Comment

28. TAK on March 26, 2012 12:08 PM writes...

To me Li+ has to be the least drug-like drug ever. As far as organic molecules, any of the anesthetics like sevoflurane would be very difficult for me to do SAR on or try to figure out PK for.

Permalink to Comment

29. CL on March 26, 2012 1:05 PM writes...

@barry: Cyclophosphamide (http://en.wikipedia.org/wiki/Cyclophosphamide) was always my favorite example when explaining the caveats of all the various rules for drug-likeness. Sure, it passes Lipinski's ROF with ease, but then it has really nasty-looking reactive groups which every decent substructure filter would throw out, but then again: it's a drug, and (because of it's selective metabolism) not even such a dirty one as one might expect.

Permalink to Comment

30. SwedenCalling on March 26, 2012 1:13 PM writes...

Good point by #7 jd. Quite a few 'uglies' listed above. Molecular beauty aside. Lipinski, Veber and derivate druglikeness rules probably do as much harm as they good good...

Permalink to Comment

31. Lu on March 26, 2012 1:28 PM writes...

May I suggest Incivek?

Permalink to Comment

32. Anonymous on March 26, 2012 2:10 PM writes...

@19 Not prejudiced at all, as long as the daily dose is reasonably low; for Linagliptin it's 2.5-5 mg q.d.

Permalink to Comment

33. Volphar on March 26, 2012 2:36 PM writes...

How many of the small molecules in this table would make it past current MedChem "best practice"?

http://en.wikipedia.org/wiki/Kinase_inhibitor


Permalink to Comment

34. C-Me on March 26, 2012 3:07 PM writes...

Glucophage (metformin)
http://en.wikipedia.org/wiki/Metformin
Not ugly per se, but weird in its simplicity and polarity. C-me

Permalink to Comment

35. Proteus on March 26, 2012 3:34 PM writes...

Nitroglycerin? I suppose it isn't *that* ugly.

Permalink to Comment

36. C-me on March 26, 2012 3:44 PM writes...

Leflunomide. http://en.wikipedia.org/wiki/Leflunomide
Its weirdness lies in the active species that it turns into in vivo: Teriflunomide
http://en.wikipedia.org/wiki/Teriflunomide
C-Me

Permalink to Comment

37. Capek on March 26, 2012 4:23 PM writes...


Adding my vote for copaxone. I nearly blew a gasket when I read the package insert.

What is the proper response to this statement:
"The average molecular weight of glatiramer acetate is 4700 to 11,000 daltons"

I want to thump my head against a blunt object.

Permalink to Comment

38. noname on March 26, 2012 4:46 PM writes...

You can't cite nat prods as ugly. Nobody made a decision to make the structure (except maybe God, and he ain't in pharma).

My fav is elesclomol, for which GSK paid $1 billion to co-develop, then jumped ship when safety concerns arose in phase 3.

A symmetric bis(acylthiohydrazide) is a beautiful thing in an ugly contest.

http://en.wikipedia.org/wiki/Elesclomol

Permalink to Comment

39. Pete on March 26, 2012 5:40 PM writes...

Good to see that a couple of folk have beaten me to Metformin. The basicity of guanidines is often a cause for concern and having 1 and 2/3 of these might be cause for even more concern. However, these guanidines share a nitrogen and metformin wold be expected (there will be a measured value but I haven't currently got access to it) be rather less basic than guanidine itself.

Permalink to Comment

40. clueless on March 26, 2012 6:20 PM writes...

Tiotropium bromide for COPD, scary looking!!

Permalink to Comment

41. Handles on March 27, 2012 1:49 AM writes...

I see your copaxone, and raise you heparin, a somewhat predictable repeating carbohydrate structure of MW 12-15kDa.

Permalink to Comment

42. Joannes on March 27, 2012 3:04 AM writes...

CTEP inhibitor Dalcetrapib seems to be a pretty good contender..

Permalink to Comment

43. Ex-Pfizerite on March 27, 2012 5:36 AM writes...

I’ll second tiotropium bromide. As someone who spent a decade in Pfizer’s hallowed laboratories, I was always much amused by the density of “structural alerts” (a Pfizerism) that had been packed into it. Spiriva partly paid all our salaries, but there’s no way anyone in Sandwich would ever have made it (and the same could easily be said of atorvastatin).

Plerixafor takes some beating for sheer weirdness http://en.wikipedia.org/wiki/Plerixafor, but my vote for all round big and ugly goes to PPI inhibitor navitoclax (ABT-263: http://cancerres.aacrjournals.org/content/68/9/3421.full). It’s fascinating to see that they overcame the (unsurprisingly) poor bioavailability of an already hefty predecessor by bolting on even more molecular weight.

Permalink to Comment

44. Formerly UCB on March 27, 2012 10:15 AM writes...

I'm with Joannes on the CETP clinical candidates. Some of the biggest clinical trials the industry has seen with compounds with logP >6. Good luck Merck...hopefully these compounds will free up a little more "drug-like" space.

Permalink to Comment

45. NorthwesternChemist on March 27, 2012 11:19 AM writes...

JWH-176

No heteroatoms - it's a hydrocarbon!

http://en.wikipedia.org/wiki/JWH-176

Permalink to Comment

46. metaphysician on March 27, 2012 4:05 PM writes...

I've never actually looked at the structure of Metformin before. Is there any particular reason it wouldn't explode if banged on with a hammer? I count more nitrogen than carbon in that molecule. . .

Permalink to Comment

47. Anonymous on March 27, 2012 5:31 PM writes...

Neglected diseases are often treated with some of the ugliest drugs: for instance stibogluconate or amphotericin B for leishmaniasis

Permalink to Comment

48. David Young, MD on March 27, 2012 11:03 PM writes...

Cyclosporin?

Permalink to Comment

49. monoceros4 on March 27, 2012 11:41 PM writes...

I vote for xenon gas. Can't get much more un-drug-like than that (although lithium salts are a close second.)

Permalink to Comment

50. glinkst on March 28, 2012 10:09 AM writes...

http://en.wikipedia.org/wiki/Promacta
Not fair to include natural products on the list. Promacta is new and I think it is oral. Looks more like a dye or a tool compound.

Permalink to Comment

51. marklar on March 28, 2012 10:23 AM writes...

Here's a monster: Sugammadex (Bridion)

http://en.wikipedia.org/wiki/Sugammadex

Permalink to Comment

52. gippgig on March 28, 2012 11:23 PM writes...

If you aren't disqualifying natural products there's always... oxygen. A diradical!

Permalink to Comment

53. Anon on March 29, 2012 7:40 PM writes...

NVC-422 In Phase II -->2-(dichloroamino)-2-methylpropane-1-sulfonic acid

What makes this even more amazing is that you put it directly on your eye! It is fancy bleach!

http://www.ncbi.nlm.nih.gov/pubmed/21422212

Permalink to Comment

54. томограф on March 31, 2012 4:41 PM writes...

Re: № 5 - я использую Fingolimod (Gylenia/FTY720) в качестве примера для химиков (я биолог), а не в том, чтобы поспешно увольнения препарат, основываясь на его структуре. Он не только не списываться быстрее, его T1 / 2, вероятно, слишком долго для его собственной пользы, больше похоже на антитела.

Permalink to Comment

55. томограф on March 31, 2012 4:43 PM writes...

Re: № 5 - я использую Fingolimod (Gylenia/FTY720) в качестве примера для химиков (я биолог), а не в том, чтобы поспешно увольнения препарат, основываясь на его структуре. Он не только не списываться быстрее, его T1 / 2, вероятно, слишком долго для его собственной пользы, больше похоже на антитела.

Permalink to Comment

56. Secondaire on April 3, 2012 9:17 PM writes...

#20: Eltrombopag

The name alone sounds like demon from a Tolkien novel.

Why the heck has nobody mentioned melarsoprol yet? It's got to be the ugliest of the ugly from several directions.

Permalink to Comment

57. Thom on April 6, 2012 8:31 AM writes...

Fosmidomycin

Broadspectrum antibiotic from the 70's, now an antimalarial

...polar as hell!

Permalink to Comment

58. Anonymous on April 12, 2012 12:07 AM writes...

this blog is getting worse

Permalink to Comment

POST A COMMENT




Remember Me?



EMAIL THIS ENTRY TO A FRIEND

Email this entry to:

Your email address:

Message (optional):




RELATED ENTRIES
How Not to Do It: NMR Magnets
Allergan Escapes Valeant
Vytorin Actually Works
Fatalities at DuPont
The New York TImes on Drug Discovery
How Are Things at Princeton?
Phage-Derived Catalysts
Our Most Snorted-At Papers This Month. . .