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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

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January 21, 2010

In Hoc Signo Non Vinces

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Posted by Derek

I am here to confess to a deep-seated prejudice, one that has been with me for many years now. I know that others feel differently, but I'm sticking to my rule: No Naphthyls.

OK, pile on me now for having a closed mind. I know that there are drugs that are more successful than anything I'll ever make that have a naphthalene in them. (At least that structure's a small one). It's just that I see a naphthyl as the worst sort of "potency through greasiness" move in drug design. They hurt your solubility, drive up your molecular weight, open you to metabolites that you may not care for, and all for what? A little activity in your in vitro assay.

I'm getting close to putting cyclohexyl on the same list, if you want to know the truth. Problem is, people make these things "just as SAR compounds". You know, they'll trowel this hunk of grease onto the side of the molecule, just to see what happens, and if it really looks good, well, they'll. . .find some way to make it better. Right. Tetrahydropyranyl instead, that'll do it. But my attitude is, why not just make the THP derivative in the first place, if that's where you're going to go?

SAR is long, and life is short. There isn't time to make everything. So I decided a long time ago that I'd try to only make structures that I could live with. That still admits a lot of weird stuff, don't get me wrong. I have functional groups on my go-to lists that make people roll their eyes. But I draw the line at flat slabs of lard. No naphthalenes.

Comments (25) + TrackBacks (0) | Category: Life in the Drug Labs


1. PharmaHeretic on January 21, 2010 9:06 AM writes...

It is not about avoiding napthyl and cyclohexyl in the scaffold per se, but using them to push up receptor binding affinity even when the benzyl- or isopropyl versions have decent/usable affinity. That is when 'good' intentions lead you on the road to ADME hell.

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2. Greg Hlatky on January 21, 2010 9:13 AM writes...

SAR's longa vita brevis est, eh?

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3. tim on January 21, 2010 9:21 AM writes...

Sorry to be the downer on the conversation, but I love naphthalenes and want to correct this spelling. I worked on 'em in grad school and always made sure people put the PHTH that makes it fun to say. naPHTHalene.

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4. chemist on January 21, 2010 9:22 AM writes...

Acyclovir (1974) is a good example of more from less. Wender has formalized his version of this as "Function Oriented Synthesis": Accounts of Chem Res, 2008, 41, 40-49. Erythtopoietin has been stripped down to a mere fragment that retains (some) function. In the spirit of truncation and brevity, I think I will

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5. Derek Lowe on January 21, 2010 10:15 AM writes...

Tim, thanks, I've corrected the spelling. And Greg, I actually thought about saying just that, but I figured that one mangled Latin tag per post was about the limit. If not well above (!)

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6. anchor on January 21, 2010 10:16 AM writes...

Derek: I agree with you completeley and some of us make very concious decision to do just that in medicinal chemistry. At our reserach company this is usually the trick people employ and that is compound bearing napthyl subunit displays superb PK properties (with little efficacy) and the management runs with that as a POC compound, only to fail later for some AE (liver enzyme elevation etc.). In my life time I have seen this play several times.

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7. Mark on January 21, 2010 10:23 AM writes...

Naproxen sodium seemed to sell pretty well!


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8. partial agonist on January 21, 2010 10:24 AM writes...

Wasn't there an approved drug or late candidate awhile back with an adamantyl group? If cyclohexyls are bad, adamantyls (cyclohexanes on steroids) must never cross your radar screen.

I used to fee similarly about t-butyls, but they do show up on occasion. Famously in terfenadine, which has the HERG/QTc issue unless your liver can chew up one of the methyls of the t-butyl to make an acid and first-pass make fexofenadine (Allegra) which has no HERG issue.

I've always avoided napthalene too. When I see it I think quinoline. If quinolines don't work too, then I get worried.

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9. Chemjobber on January 21, 2010 10:54 AM writes...

Not the non-classically trained among us, the Google tells me that the post title is translated as "by this sign you will not conquer."

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10. Chemjobber on January 21, 2010 10:57 AM writes...

Er, that's "note to the blah,blah".

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11. Alex on January 21, 2010 11:16 AM writes...

And what about propanolol?

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12. PJ Hansen on January 21, 2010 11:18 AM writes...

Classically trained? I thought Derek was just quoting the Pall Mall label.

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13. Biologist on January 21, 2010 11:26 AM writes...

my apologies for digressing but one could take this as a comment on the title of your blog ...
just saw the list of the "best 100 companies to work for at ...
not a single American pharmaceutical company is on the list if I am not mistaken. In biotech, Genentech made it, and the Scandinavians made it (Novo Nordisk)
... awful times ...

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14. Dr Evil on January 21, 2010 11:50 AM writes...

Partial agonist: Perhaps you're thinking of memantine, a monster if ever I saw one! Back to the original post, I always wonder how much time is wasted playing the numbers game, developing SAR on compounds that will never be progressed is a luxury we can't afford these days. Time to get out of the in vitro activity mindset and into an in vivo mindset where we think about the implications of dubious functionalities that only give a smigin more activity.
Sorry, time to get off my soapbox.

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15. hell to the chief on January 21, 2010 1:18 PM writes...

#8 and #14

Saxagliptin (onglyza) is also a proud bearer of an adamantyl group.

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16. barry on January 21, 2010 2:20 PM writes...

By this same logic, would you rule out making peptides, peptide aldehydes and peptide nitriles at the start of a protease inhibitor program? That's where x-ray crystallography starts, and med chem then gets away from the objectionable moieties. We all know of cases where someone tried to push a tool compound into development, but that won't stop me from making tools.

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17. nobody_of_consequence on January 21, 2010 4:20 PM writes...

I always felt that the grease on Naproxen contributed to its long half life. That's how it can be 'all day strong' in the ad.

#8, #14, #15

The DPP-4 inhibitor Galvus has an adamantyl group

I would argue that it is aryl + basic nitrogen that causes hERG. It is the acid that the t-butyl turns into that saves fexofenadine.

Isn't everything bad ... drugs are selective poisons after all.

It is the biological rather than the chemical profile that is important. Banning certain chemical classes: nitro, napthyl, anilines seems like overly crisp thinking for something as squishy as biology.

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18. retread on January 21, 2010 6:07 PM writes...

Symmetrel -- amantadine hydrochloride is all CH and CH2 groups except for the amine.

It is amusing that my undergraduate advisor (Paul Schleyer) subsequently had a lot to do with a synthesis for adamantane (note the slightly different spelling from the pharmacological name) and that after I left organic chemistry and became a neurologist, I used a derivative (amantadine hydrochloride -- Symmetrel) as an adjunctive treatment for Parkinsonism. While the compound doesn't look anything like dopamine (the neurotransmitter deficient in Parkinson's disese), it causes dopamine release from neurons.

Coincidences like this are why I don't read novels. Life is far more fantastic.


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19. cliffintokyo on January 21, 2010 8:50 PM writes...

#18 Retread
Nothing is ever a coincidence; you should read more novels!

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20. Dan on January 21, 2010 11:46 PM writes...

Here's another one from my former company. My supervisor at the time played a large part in the early development of the compound. And I still have a shirt with AMG 073 on it before it was named.

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21. Jetset on January 22, 2010 7:42 AM writes...

Now while I agree in priciple with the rationale for hating a naphthyl group, if we're going to start a witch hunt for unfriendly groups aren't we going to end up going round the "anilines are all genotoxic" route again.

A compounds properties and therefore it's biological activity, DMPK, toxicity etc. etc. are all defined by the molecule as a whole - sure you can have reactive metabolites but if the compound doesn't hang around long enough in the liver to get whacked by P450's then it might not ever see that intermediate, get my drift?

If you want a good example of why you don't throw the baby out with the bathwater check out singulair, lamictal, spiriva, the list goes on. Sure, don't base your whole libraty on anilies, naphthalenes, tert-butanols and epoxy beta-lactams, but you never know you might just get that hit which pushes you in the right direction.

P.S. Anyone who automatically throws out a compound with logP>4 and mw>400 should check out the top selling lipid receptor drugs and wince.

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22. dddd on January 22, 2010 8:00 AM writes...

@2: "SAR's longa vita brevit"

Genius :)

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23. Chemjobber on January 22, 2010 9:19 AM writes...

21: I've heard folks say the cutoff for *leads* should be logP

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24. Chemjobber on January 22, 2010 9:21 AM writes...

er, that's logP less than 3.5 and mw less than 350.

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25. LWH on January 25, 2010 10:23 AM writes...

Well done Derek. I think you've touched on 2 fundamental truths of drug discovery.

First, I agree with you that the "oh, it's just a data point" attitude is wasteful. Sampling extreme parts of chemical space is a great idea if you have lots of time, but drug discovery usually requires a more greedy method. If you've ever played Mastermind, you'll know that one of the most effective strategies for finding the hidden pattern is to make sure your guesses are all possible solutions.

Second, making compounds with obvious liabilities encourages teams to ignore those liabilities and put off solving those problems. The classic "let's focus on activity and solve the rest later" syndrome. Again, some judicious sampling risky chemical space is realistic, but should be kept to a minimum.

And let's not forget that the exception does not disprove the rule. There are many examples of drugs with structure that usually come with liabilities. It just means that we should not make it a habit of ignoring the warnings of the past.

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