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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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September 15, 2011

Terra Slightly Less Incognita

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Posted by Derek

Back last year I did a brief post about how much not-so-exotic druglike chemical matter has never been explored. My example was substituting heteroatoms into the steroid nucleus - hard to get much more medicinally active than those, but most of the possible variations have never been made. Structurally they're right next door to things that have been known for decades, but they're largely unexplored (which is many cases is because they're not all that easy to make).
200px-Abiraterone.svg.png
The RSC/SCI symposium called my attention to something in this exact class, abiraterone, a CYP17 inhibitor. This was discovered at the Institute for Cancer Research in London, and after several steps through the development world has ended up with J&J. It was approved by the FDA earlier this year for some varieties of prostate cancer.

So there's an example of a sorta-steroid making it all the way through. If intelligent (and oddly motivated) aliens landed tomorrow and forced me to use their advanced organic synthesis techniques to generate a library of unique structures with high hit rates in drug screens, I think I might ask them if they knew how to scatter basic amines, ethers, sulfonamides and so on in and around the steroid nucleus. I offer that advice free of charge to any readers who might find themselves in a similar situation.

Update: as per the comments, compare Cortistatin A for another, more highly modified steroid nucleus with an aromatic heterocycle hanging off it.

Comments (16) + TrackBacks (0) | Category: Cancer | Chemical News


COMMENTS

1. Hap on September 15, 2011 9:31 AM writes...

It looks a lot like a normal steroid-cored variant of cortistatin A. I wonder if it does anything similar.

Permalink to Comment

2. Ich Dich on September 15, 2011 10:52 AM writes...

From the wikipedia article on Abiraterone comes "A course of treatment costs $40,000"

Now, I understand steroid chemistry is a bitch, but still seems like a lot for a small molecule. Anyone with ideas on why this is?

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3. anon the II on September 15, 2011 11:12 AM writes...

My boss many years ago, was convinced that an indole was a good isoster of a phenol and so he had lots of people fusing pyroles onto any drug that had a phenol (think estrogen). I don't remember any that panned out, so they never saw the light of day.

Steroid-receptor binding is often very tight although steroids are often fairly rigid. One reason for this is that mother nature was able to vary both the steroid and the receptor to get to the right place. We don't have that luxury.

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4. anon on September 15, 2011 12:19 PM writes...

related Natural products and synthesis of interest

http://pubs.acs.org/doi/abs/10.1021/jo00122a074

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5. Steroid Chem on September 15, 2011 12:30 PM writes...

The synthesis is fairly easy and starting materials are easily available. 40k per treatment seems a bit too high in this case.
@ anon the II: These days in Med. Chem., everyone wants a pyridine inside the molecule. It´s crazy.

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6. NodrugsNoJobs on September 15, 2011 12:45 PM writes...

definitely easy to make - the trouble is when you wish to modify the steroid backbone itself, ie - putting heteroatoms into the backbone. It can be done but is quite limited. Here you have the readily accesible C-17 position, probably used something like DHEA for the starting material. The cost of the drug usually doesn't have too much to do with the cost of producing it but rather what the value proposition is to the payor. If your drug has a clear economic cost benefit all the way up to price A then you are likely to charge price A. it will be generic eventually and dirt cheap for all of the future of mankind until a better drug replaces it. J and J paid something like at least 1 billion for the drug and that was pre-approval meaning they sunk more money into it and also took a risk it wouldn't be approved. Not sure what they should charge but in general, late stage prostate cancer patients don't live so long so those who have to use this drug will not be on it for too long (

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7. HelicalZz on September 15, 2011 12:47 PM writes...

Well, I think you just made the case for why this isn't done. It is a bit to 'obvious to those skilled in the art'. So by all means develop such a drug, but with the understanding in a Hatch-Waxman ruled world that it is going to get challenged down the road. Generic companies have very little to lose and plenty to gain in doing so. Care to pitch a compound / program that may well only have 5 years of data exclusivity within which to recoup development and create a profit -- I wouldn't. And Ich Dich, did this answer your question?

Zz

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8. milkshake on September 15, 2011 12:51 PM writes...

@steroid chem: I don't. In my experience 4-pyridyl substituent put onto a large greasy rigid molecule is likely to give you hard-to-dial-out trouble (CYPs inhibition and QT prolongation)

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9. NoDrugsNoJobs on September 15, 2011 1:07 PM writes...

milkshake - I reckon the pyridine or a similar chelating group needs be there because this compound is in fact a CYP-inhibitor, thats its MOA

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10. Derek F on September 15, 2011 1:10 PM writes...

On the cost of abiraterone as therapy, it's never really about cost of manufacture unless you're talking about aspirin or something like it, it's about cost of alternatives (Provenge?), cost of getting the drug approved, expected number of patients, etc. And abiraterone goes off-patent in early 2014 in the US (though there's probably an extension application pending, but I don't see it in PAIR) and NCE exclusivity expires in April 2016, so there's not a lot of time to cash in.
I don't agree about "obvious to those skilled in the art" (@HelicalZz) - while it may be obvious to think about making substitutions, finding a useful substitution is another thing altogether, and it is that which makes compounds such as abiraterone patentable.

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11. Hap on September 15, 2011 1:13 PM writes...

The cephalostatins (see a group meeting PDF on one) aren't particularly modified steroids (or steroid dimers), but they took an awful lot of work to make, and I don't know that they came to much. The cyclopamines are a little more modified (contracted C ring, expanded D ring), but neither class has much in the way of heteroatom insertion into the framework.

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12. iluvSteroids on September 16, 2011 7:59 AM writes...

This looks a little bit like a limonoid (European Journal of Organic Chemistry, 2011: 19–46), an oxidized steroidal system with a furan hanging off of C17.

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13. iluvSteroids on September 16, 2011 8:01 AM writes...

This looks a little bit like a limonoid (European Journal of Organic Chemistry, 2011: 19–46), an oxidized steroidal system with a furan hanging off of C17.

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14. metaphysician on September 17, 2011 9:03 AM writes...

Mars Needs Biochemists? Maybe they pay better than China. . .

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15. David Young MD on September 17, 2011 10:54 AM writes...

So, J and J purchased Cougar Pharmceuticals for one billion dollars to get their hands on Abiraterone. Therefore the high cost. It seems like a more tangible way of treating prostate cancer than Provenge. And to approve Abiraterone so that it has to be used after a patient has had chemotherapy is total unethical. (The FDA can make unethical approval language that would never pass an IRB.) It will be used before chemotherapy and it makes sense to do so.

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16. researchfella on September 18, 2011 11:48 AM writes...

@15 - presumably the FDA-approved indication for Abiraterone is based on how the Phase 3 trials were done, and with which patient population, not on which patients "might" benefit most. But there will likely be off-label use, and other trials are in the works.

@HelicalZz - if you want to think about "obvious to those skilled in the art", take a look at the Phase I/II entry TOK-001 from Tokai for this indication. I think it's the same steriod with a pyridine mimic.

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