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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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« The Scientific Literature Gets Kicked Around | Main | Fifty Years of Med-Chem Molecules: What Are They Telling Us? »

September 12, 2011

From the RSC/SCI Symposium: A Med-Chem Anomaly

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Posted by Derek

Well, actually, this might not be an anomaly. Medicinal chemists will have heard of the "magic methyl" effect, where small changes can make a big difference in affinity for a drug candidate. This morning I heard an interesting talk by Phil Sanderson of Merck on allosteric Akt inhibitors for cancer. I won't go into all the kinase-ness, although it was definitely worth hearing about. What caught my eye was something he mentioned at the end of the talk. The first compound below was an early screening hit in their work, something that had been in Merck's files since the early 1970s. After a huge amount of work over many years, which you can follow though the literature if you like with a search for "allosteric" and "Akt", they found that four-membered rings were very useful in the structures. Going back to the original structure and adding that same modification to it improved its potency by roughly 100-fold.
One methylene group! You wonder what might have happened if they'd done that early in the project, but as Sanderson correctly noted, no one would have done that (it's synthetically tricky; no one would have put in the time). And they don't have any structural information that seems to explain this effect, he says. So if you're looking for an illustration of what makes medicinal chemistry the wild ride it is, you've got an excellent one here.

Comments (20) + TrackBacks (0) | Category: Life in the Drug Labs


1. myma on September 12, 2011 9:28 AM writes...

Looks like a good hERG inhibitor to me

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2. Curious Wavefunction on September 12, 2011 9:32 AM writes...

Nice data point. The difference could very well be conformational. A cyclobutane will have pronounced axial and equatorial preferences for the NH2 and aryl groups with a barrier of at least 1-2 kcal/mol. A gem dimethyl substituent will probably place the the two in a wholly different preferred conformation. The former conformation with the cyclobutane could in turn be much more favorable for interacting with the protein.

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3. Looks like on September 12, 2011 10:11 AM writes...

An aggregator to me.

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4. Chemjobber on September 12, 2011 10:20 AM writes...

Isn't there a Carreira ACIE paper on oxetanes that's somewhat similar?

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5. Quintus on September 12, 2011 10:48 AM writes...

Hi Chemjobber,
Isn't there a Carreira paper on everything?

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6. anchor on September 12, 2011 11:33 AM writes...

#1 also seems like COX2 inhibitor and may be also attracted to estrogen receptors.

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7. Courtney H on September 12, 2011 11:43 AM writes...

Reminds me of this puzzling (to me at least) paper on the effect of conformational constraints on protein-ligand interactions:

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8. Vader on September 12, 2011 12:08 PM writes...

"they found that four-membered rings were very useful in the structures."

Lucky four-leaf clover?

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9. Hap on September 12, 2011 12:52 PM writes...

Carreira's been focusing on various flavors of 3-substituted oxetanes for med chem uses - see J. Med. Chem 2010, p. 3227.

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10. Pete on September 12, 2011 2:46 PM writes...

As Wavefunction points out, the origin of this difference could be conformational. If, however, this is indeed the case it will be due to differences in the torsional potential about the bond that links the aromatic ring to the quaternary carbon rather than axial/equatorial preferences of substituents. It can be helpful to think about axial/equatorial differences as determining the position of the 'inserted' methylene. When considering energetics, remember that the primary amine will be protonated under normal physiological conditions.

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11. RD on September 12, 2011 3:26 PM writes...

The cyclobutyl is more compact than the dimethyl. The pocket maybe just a belly button. And yes, I'd calculate HERG for that series, unless you can wrangle the real data.

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12. jim on September 12, 2011 3:34 PM writes...

tee-hee...funny conversation going on at the 'Totally Synthetic' blog. Not every day that Andy Kaufman is referenced at a chemistry site

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13. Anonymous on September 12, 2011 4:03 PM writes...

Well, if they're publishing it I think we all know the value of the molecule, however, the observation is interesting. Seems that Merck has a tendency to drag programs on and on and on...only to arrive at this finding (as an example). Only the energizer bunny has more stamina...

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14. Useless Schlenk Line on September 12, 2011 9:32 PM writes...

@ Curious Wavefunction and Pete


That's not what happens. I am pretty convinced that there's an isoleucine somewhere near the active site.

The the terminal methyl of the isoleucine probably fits and locks itself in the cyclobutyl ring. Like a hook! Needless to say, the gem-dimethyl can't grab the isoleucine, explaining the lack of potency.

LOL :-)

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15. Pete on September 12, 2011 10:51 PM writes...

My comment was simply that if the effect was indeed conformational then I didn't agree with Wavefunction. Establishing that differences in SAR are due to conformational effects is not always that easy. If the torsional potentials about the aromatic/quaternary carbon bond were very similar, I would suspect that other factors were more important. Locking the the terminal methyl of the isoleucine in the cyclobutane ring is not a convincing rationale for the observed SAR although it might be a way forward if you're working on cold fusion.

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16. Chris Swain on September 13, 2011 1:36 AM writes...

It is an interesting observation. Is there perhaps an electrostatic interaction with the protonated amine that is somehow stabilised by the cyclobutyl ring?

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17. BRSM on September 13, 2011 2:01 AM writes...

I thought the 'magic methyl effect' was a slow and painful death from methylation.

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18. CB on September 13, 2011 8:01 AM writes...

Couldn't it be as well as a conformational/steric thing in the active site an entropy thing? The cyclobutane has less degrees of freedom, so it looses less energy when bound.

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19. Curious Wavefunction on September 13, 2011 10:50 AM writes...

Useless Schlenck: I hope you are joking; there's no space in a cyclobutane to accommodate a methyl. Also, a methyl could have a similar hydrophobic interaction with a cyclobutane and another methyl. In the absence of other data it's hard to say.

In any case, this is one of those typical med chem scenarios in which there's a multitude of possible factors responsible for an observed change in potency. Could be any one of them; I just offered a possible conformational explanation. I do agree that the torsional potentials could be different but I don't see why an ax/eq energy difference would be ruled out. Entropy could also play a role (with the cyclobutane constraining things a little more than the gem dimethyl). As usual, life is a 2 kcal/mol game so anything's possible.

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20. Anon on September 13, 2011 1:04 PM writes...

Too bad science-naive management too often still thinks of drug discovery as an assembly line.

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