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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: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« One For the Brave | Main | Bright Lights and Applause? »

November 4, 2007

Nerve, Lots and Lots of Nerve

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Posted by Derek

Sometimes I think that my chemical intuition is all haywire. Medicinal chemists, after they've seen several projects succeed and fail, accumulate a set of prejudices and opinions about what sorts of molecules are more likely to lead to good things (and what sorts are more likely to waste your time).

Many of these are uncontroversial: no one, for example, is going to tell you to load up your molecule with plenty of guanidines or acid chlorides. But there's a big middle ground where the arguing starts. Sulfonamides - like 'em or hate 'em? How about ureas? Tetrazoles as carboxylic acid isosteres? All of these groups are found in marketed drugs, but you can find experienced medicinal chemists whose noses wrinkle at them, because they feel that too many such compounds fail to make them worthwhile. Me, I don't like napthalenes, and I never put one on a drug candidate molecule. The next multibillion-dollar drug will probably have one, just wait.

mt477kv6.jpgBut the reason I think my intuition is off is the molecule shown to the right (and thanks to KinasePro for bringing it to my attention. Where do I start? That screwy thiopyran ring? With its screwy thioketal? The multiple methyl esters, when I wouldn't even want to have one? Man, is that one ugly structure. But, as KP points out, the company that developed this shimmering vision is trying to sell it. That's right, they actually have the nerve to ask for money for this beast. So what's wrong with them? Or is there something wrong with me, because I'd never have that kind of gall, not even if I practiced for years. . .

Comments (19) + TrackBacks (0) | Category: Drug Development


COMMENTS

1. ChemSpiderMan on November 4, 2007 10:39 PM writes...

Did you draw that structure yourself? If so, can you send me the molfile so that I can submit to the Chemspider database. If you didn't draw it can you point me to the page you cropped it from? Thanks

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2. SBC123 on November 4, 2007 10:43 PM writes...

Derek, what is wrong with guanidines?

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3. Cat Herder on November 4, 2007 11:33 PM writes...

I especially like the Michael acceptors... Brilliant! Do you know if the sellers have some sort of in vivo or metabolic data to defend themselves with when they show up trying to pitch this thing?

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4. Petros on November 5, 2007 3:13 AM writes...

Not all compounds that lokk like Michael acceptros behave as usch under physiological conditions- I had the same problem with objections to a series of compounds. Admittedly they were not attrcative looking structures!


As for MT-477
"The following is a brief description of MT477 and is updated periodically to reflect the status of pre-clinical studies and licensing activity.

Product Family
The MT477 family of therapeutic compounds was screened from tens of thousand of designed candidates with an optimal activity profile against non-small cell lung cancer, using Medisyn’s Forward Engineering™ in silico techniques. MT477 predictions for activity and specificity have been validated in vitro with the National Cancer Institute (NCI) 3-cell and 60-cell line testing. In addition to identifying active chemical analogs, Medisyn has designed “property analogs” as backup lead candidates – these are chemically diverse structures possessing the same therapeutic properties as MT477. Drug-like MT477 and its analogs show remarkable promise and potential as candidates for pre-clinical and clinical evaluation."

http://www.medisyns.com/MT477.htm


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5. oleg on November 5, 2007 10:02 AM writes...

ChemSpiderMan,

Here are smiles copied from Kinasepro website http://kinasepro.wordpress.com/2007/10/27/mt-477/

O=C(OC)C(SC2(C(C(C=CC=C4OC)=C4N(C(CN5C(CCC5=O)=O)=O)C(C)3C)=C3SC(C(OC)=O)=C2C(OC)=O)S1)=C1C(OC)=O

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6. MolecModeler on November 5, 2007 10:08 AM writes...

Wow, a kinase (?) compound that kills NCI cell lines! That is an amazing achievement to be sure. Show me some 2 week animal tox and in vivo DMPK.

What's that? Your dog ate that data? Oh, what a pity.

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7. Wavefunction on November 5, 2007 10:17 AM writes...

I wonder if the multiple esters (or at least a few of them) are for prodrug purposes

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8. Jose on November 5, 2007 11:37 AM writes...

Wavefunc, I think using the term "prodrug" in any context relating to that monstrosity might be rather dodgy.... :)

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9. Ai-yi-yi on November 5, 2007 2:11 PM writes...

Wow. I have to agree, that is one ugly looking structure. But just because they are selling it doesn't mean anyone is buying. Interestingly, Lipinski is on their Scientific Advisory Board. I don't have to look at this structure for too long to recognize it doesn't meet Lipinski's rules.

I also have to admit, however, that when I first saw SAHA I thought there was no way it could be a drug. And when I first saw Sutent-like analogs which turn rotovaps lots of pretty colors I didn't think that class had much of a chance either. Still, I would guess they refer to this by number as much as possible - hoping that the BD guys evaluating it don't know anything about chemistry. To many of them a compound is a compound......

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10. Molecular Geek on November 5, 2007 2:19 PM writes...

The design of that one is much too amateurish for it to be a pro anything ;-)

MG

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11. Anonymous on November 5, 2007 6:48 PM writes...

This is the successor to combichem library sales. Medisyn and other claim they can fix your problems for a very large fee. Saw a proposal of theirs to fix an existing program and could not believe what they claimed and charge. I guess you have to pay for that 85% succes rate.

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12. milkshake on November 5, 2007 7:51 PM writes...

Sutent-class compounds really are unpleasant to work with (very poor solubility, easy cis-trans equilibration, yellow everything) and it takes some patience to make them right, especially on large scale. The second problem is metabolism - you can make the basic pyrrole-oxindole scaffold selective and very potent against a number of kinases of interest - but for a price of adding another large functional group like benzyl sulfone or cyclohexane ring or carboxamide - and this addition always makes the compound undruggable (solubility, metabolism issue). So Sutent is probably quite close to what can be done with the scaffold.

Lipinski on advisory board means nothing: The big names are there on the list to impress the investors. Twice a year they are flown in, to attend a half-day of boring presenations and for that they get generous stock option package. No responsibility. In my first combichem company we had Merrifield and Whitesides on the board. (Merrifield was shy, polite and did not interfere, Whitesides was sometimes decoherent and combative. Either way, it was not clear to what effect their random advice had on the management decisions.)

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13. Ian Musgrave on November 5, 2007 10:44 PM writes...

MolecModeler wrote:

Show me some 2 week animal tox and in vivo DMPK

While this isn't animal tox, 1mg/kg MT477 given intraperitonealy to mice over 28 days was equieffective with 2 mg/kg cisplatin in slowing the growth of H226 tumour xenogafts (and substantially worse at slowing A431 xenografts, but still slowing tumour progression).

It's still a long way to go yet, and many far more promising drugs have fallen after this stage, but it does work in an in vivo model.

Jasinski P, et al., A novel quinoline, MT477: suppresses cell signalling through Ras molecular pathway, inhibits PKC activity, and demonstrates in vivo anti-tumor activity against human carcinoma cell lines. Invest New Drugs. 2007 Oct 24;

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14. TX Raven on November 6, 2007 5:37 AM writes...

Well... I am sure somewhere out there there is a business development group which is 1 deal short of their corporate goal. Would not doubt for a second before pissing off 10 million of corporate money buying such kind of crap to make that end of the year bonus!

I have been horrified by looking at some of the compound structures my company's business guys were thinking of buying!

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15. Cowboy on November 6, 2007 3:22 PM writes...

Derek, what's wrong with naphthalene in drug molecules? Propanolol has one attached to an oxygen.

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16. enan on November 6, 2007 8:46 PM writes...

Wow, that is an ugly one, for sure. I think I will make a model of it tomorrow. Maybe it is prettier in 3D.

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17. tom bartlett on November 7, 2007 8:23 AM writes...

"Maybe it is prettier in 3D."

Or after a few drinks.

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18. Hap on November 7, 2007 2:27 PM writes...

A vinylogous ortho-thioester - that's something you don't see everyday.

The multiple esters probably help to shut down sulfide oxidation by electron-withdrawal and steric hindrance, but in that case it might undergo nucleophilic substitution at the thiopyran if it's electron-deficient enough, and then it's off to the races. An alternative mode might be lots of single-electron chemistry, which would also not go well. It did survive at least one in vivo model, though, so maybe these things don't happen in real life.

Maybe they're hoping that some drug company wants to get rid of some pharmacologists by turning their brains into porridge.

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19. Alex on November 8, 2007 2:20 PM writes...

No naphthalenes ? - Naproxen as well has a naphthalene ring !

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