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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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October 3, 2012

A Lovely Petite Compound

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Posted by Derek

I can't resist pointing out this compound, which recently showed up in J. Med. Chem.. Now, that's a Bcl-2/Bcl-xl inhibitor, the star of the protein-protein interaction world, and there's probably never going to be a nice-looking compound that does the job in that system. The interacting surfaces are too wide and too shallow; it's a real triumph that people have compounds for this system at all. But people have, and there are compounds in the clinic.
But man, will you look at the things. This is one from Bristol-Myers Squibb the University of Michigan, and it is a beast in all directions. It weighs a mere 811 daltons, and is actually one of the more svelte compounds in the paper. Solubility, formulation, absorption, clearance. . .it all looks like fun. But we may well have to start learning how to deal with compounds like these, so we'd better steel ourselves.

Comments (33) + TrackBacks (0) | Category: Cancer | Chemical News


1. Chemist For Life on October 3, 2012 12:28 PM writes...

Rule-of-five; not just broken – smashed into pieces!

The current trend (or necessity) for exploring (and modulating) peptide-protein or protein-protein interactions, has forced us to rethink drug chemical space. I think these types of compounds are certainly the outliers (for now), but I agree may become increasingly common in the future.

Poor PK, rubbish solubility...bring it on! Just forces us to be more creative…

Remember, necessity is the mother of all invention.

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2. ddddddd on October 3, 2012 12:42 PM writes...

Crikey that's an ugly molecule!

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3. noko marie on October 3, 2012 12:56 PM writes...

Lunchtime for the cyps!

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4. partial agonist on October 3, 2012 1:10 PM writes...

It looks a lot like ABT-263, aka navitoclax, which is orally bioavailable despite similar extreme ugliness.

Its structure is a quick google image search

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5. milkshake on October 3, 2012 1:23 PM writes...

that nitrobenzenesulfonamide piece is a particularly revolting touch...

for other monsters, look up structures of itraconazole and posaconazole

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6. Chemjobber on October 3, 2012 1:46 PM writes...

Hey, rule of five: drop dead.

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7. Jon on October 3, 2012 2:34 PM writes...

I must be a process chemist by now, because my only thought when I looked at that molecule was "I've seen worse things to have to scale up."

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8. Anonymous on October 3, 2012 2:38 PM writes...

I did some work in this area and I agree, the compounds are very different from traditional med chem. This one looks to be based on Hamilton's work, which didn't have a piperazine in the center but a 3rd phenyl ring! He (and others) subsequently experimented with pyridines and other heterocycles to improve the aqueous solubility. Interesting concept and compounds, I'm curious to see where these lead.

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9. Jim on October 3, 2012 3:08 PM writes...


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10. David Borhani on October 3, 2012 3:22 PM writes...

VERY close to ABT-737 (predecessor of ABT-237). BMS lost the CO at the sulfonamide, and threw on some extra stuff (substituted pyrrole) to replace the biphenyl of ABT-737.

Looks like the Abbott patent lawyers weren't thinking sufficiently out of the box to cover (at the nearly identical core of) this BMS compound...

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11. David Borhani on October 3, 2012 3:29 PM writes...

Make that University of Michigan, not BMS (and licensed by Ascentage Pharma).

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12. anon the II on October 3, 2012 3:34 PM writes...

The other end reminded me of Lipitor, sorta. Maybe that isopropyl-Michigan connection.

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13. Josh on October 3, 2012 3:42 PM writes...

What a mess. You gotta love the nitro, aryl thioether, pentasubstituted pyrrole and an acid thrown in just to put the final in the cell permeability coffin. Blah

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14. David Borhani on October 3, 2012 3:47 PM writes...

@12 -- Yes, this is made clear in their earlier paper:

Zhou et al. J. Med. Chem., 2012, 55:4664
DOI: 10.1021/jm300178u
Design of Bcl-2 and Bcl-xL Inhibitors with Subnanomolar Binding Affinities Based upon a New Scaffold

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15. barry on October 3, 2012 3:58 PM writes...

as we wander farther from Lipinski-space, we feel ever more acutely the lack of a general technology to measure cytosolic concentrations of "small" molecules. At least this one has a likely fluorophore--one might be able to estimate intracellular concentrations by fluorescence microscopy?

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16. David Young on October 3, 2012 6:39 PM writes...

Speaking of interesting molecules, what do you think of Xtandi(Enzalutamide)?

Four fluoride atoms and a Sulfur not-to-mention a nitrogen-carbon triple bond.

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17. AnonAnon on October 3, 2012 6:51 PM writes...

Have extensive stability studies been done on this compound? What happens to its efficacy if that thiophenyl ether gets oxidized? It this sucker even water-soluble?

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18. Chemist For Life on October 3, 2012 7:17 PM writes...

@16 - The Medivation molecule looks very reasonable from a drug perspective.

The nitrogen-carbon triple bond is known as a "nitrile" functional group, and these are normally are pretty benign. As for the four fluorine atoms, the incorporation of a trifluoromethyl or simple fluoro moiety is often employed to help improve PK (for example to modulate metabolic clearance).

Now for an example of where fluorine was used, shall we say, very liberally - I would refer you to "anacetrapib" which has 10 of the suckers!

Anacetrapib is a CETP inhibitor targeting dyslipidemia, and is currently in Phase-III. It remains to be seen if anacetrapib makes it all the way...

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19. jd on October 3, 2012 7:47 PM writes...

Yes, why is this called a BMS compound?

This comes out of Shaomeng Wang's lab at Michigan. This is actually follow up to a previous ACSMCL paper.

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20. gippgig on October 3, 2012 8:29 PM writes...

Return of the sulfa drug! Of course, the nitro (or one of the other bulky substituents) might destroy the antibacterial activity (anybody bother to test this?).

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21. Anonymous on October 3, 2012 9:34 PM writes...

And yet another ugly one (JNK inhibitor).

Trying to develop such a compound for IV delivery is nonsense. What were they thinking....but then again it's from Roche so thought is optional! LOL

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22. MTK on October 4, 2012 7:56 AM writes...

People love to bash the Rule of 5 which never ceases to crack me up.

Of course I recognize that what they're really bashing is not the rule itself, but the way it's been utilized, or perhaps canonized.

Regardless, it's not surprising that something such as looking at disrupting protein-protein interactions may be anti-Rule of 5 because the set of molecules use to formulate the rule did not include molecules that do that.

Instead of jumping up and down in glee ("Rule of 5 broken, yippee!)maybe we should just rationally say, Rule of 5 may not be applicable in this area.

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23. Pete on October 4, 2012 8:17 AM writes...

And just how strong are the links between properties and outcomes? There are plenty of Ro5-compliant compounds that are not drugs? Does Ro5's HB donor-acceptor asymmetry not raise any questions?

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24. RTW on October 4, 2012 9:00 AM writes...

17 Annon the II - Yes indeed this does look a lot like a Atorvastatin but the pattern around the Pyrrole ring is different. Replace that carboxylic acid with an Anilide amide, and attach the sugar in place of the methyl group and I bet that might have some Statin like activity! Might even make it more soluble.

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25. Chemist For Life on October 4, 2012 11:50 AM writes...

@ 22 MTK - I don't think we are particularly gleeful that the "guidelines" known as the 'Ro5' have been broken in this case. Actually, I believe that the 'Ro5' is more often than not quite useful in helping generate molecules with more optimal physicochemical and ADME profiles etc - a very reasonable approach if you ask me.

The important point here, is that we are acknowledging that in order to be more creative in discovering new medicines, the industry is being forced into looking at a different (and less familiar) class of target, for instance large protein-protein interactions. Such targets might well require a different class of compound, whether it be (not so) small molecules, or peptides.

Not all biological targets respond well to small (

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26. barry on October 4, 2012 12:06 PM writes...

if this compound can give an informative cocrystal structure by x-ray diffraction with the target protein, it could be a valuable tool to design a better drug candidate. As it stands, it faces all the problems that Lipinski enumerated. That doesn't mean that it's a non starter. But formulation and absorption will be problematic at best. For a cytosolic target these are serious problems.

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27. Chemist For Life on October 4, 2012 12:26 PM writes...

Regarding my previous post - for some reason the last sentences did not post properly...

But you get my point.

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28. Hap on October 4, 2012 12:39 PM writes...

27: You probably used a less-than sign in your post ("...less than X Da....") - HTML sees the less-than sign as a lead character to its commands and so doesn't print anything following it. For a displayable less-than sign, you need to write (ampersand)lt [(ampersand)gt = greater-than] so that HTML won't cut off the rest of your comment. For example: "< 3 billion dollars..."


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29. MTK on October 4, 2012 3:28 PM writes...

Fair enough Chemist for Life.

And I wasn't commenting on you specifically, just in general. I see a lot of Rule of 5 bashing, but your sentiments in comment 25 are about what I think also.

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30. Chemist For Life on October 4, 2012 3:43 PM writes...

@28 Hap - You are smart, that's exactly it. Thanks for the insight!

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31. Hap on October 5, 2012 6:38 AM writes...

No, not really - that's happened here before.

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32. DrSnowboard on October 5, 2012 6:52 AM writes...

"Lipinski's rule states that, in general, an orally active drug has no more than one violation of the following criteria:...blah".
Note that 'in general' , that "orally active" plus of course the unstated "that is transported by passive diffusion" ...
If we all could predict solubility and permeation by looking at a structure, what would we need those fancy calculations for?

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33. Mr. Fixit on October 5, 2012 7:14 AM writes...

Why do the think Ro5 is the only set of rules that can work. As somebody who has worked on med chem in the macrocycle field for a few years now, I can tell you there are orally bioavalible larger molecules out there. Ro5 was only an observation, maybe the data set was too small.

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