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Derek Lowe The 2002 Model

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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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December 6, 2006

Bigger And Greasier

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Posted by Derek

Several people have remarked on how large and greasy a molecule torcetrapib is, and speculated about whether that could have been one of its problems. Now, I have as much dislike of large and greasy molecules as any good medicinal chemist, but somehow I don't think that was the problem here.

For the non-medicinal-chemists, the reason we're suspicious of those things is that the body is suspicious of them, too. There aren't all that many non-peptidic, non-carbohydrate, non-lipid, non-nucleic acid molecules in the body to start with - those categories take care of an awful lot of what's available, and they're all handled by their own special systems. A drug molecule is an interloper right from the start, and living organisms have several mechanisms designed to seek out and destroy anything that isn't on the guest list.

An early line of defense is the gut wall. Molecules that are too large or too hydrophobic won't even get taken up well. The digestive system spends most of its time breaking everything down into small polar building blocks and handing them over to the portal circulation, there to be scrutinized by the liver before heading out into the general circulation. So anything that isn't a small polar building block had better be ready to explain itself. There are dedicated systems that handle absorption of fatty acids and cholesterol, and odds are that they're not going to recognize your greaseball molecule. It's going to have to diffuse in on its own, which puts difficult to define, but nonetheless real limits on its size and polarity.

Then there's that darn liver. It's full of metabolizing enzymes, many of which are basically high-capacity shredding machines with binding sites that are especially excellent for nonpolar molecules. That first-pass metabolism right out of the gut is a real killer, and many good drug candidates don't survive it. For many (most?) others, destruction by liver enzymes is still the main route of clearance.

Finally, hydrophobic drug molecules can end up in places you don't want. The dominant solvent of the body is water, of course, albeit water with a lot of gunk in it. But even at their thickest, biological fluids are a lot more aqueous than not, especially when compared to the kinds of solvents we tend to make our molecules in. A hydrophobic molecule will stick to all sorts of things (like the greasier exposed parts of proteins) rather than wander around in solution, and this can lead to unpredictable behavior (and difficulty getting to the real target).

That last paragraph is the one that could be relevant to torcetrapib's failure. The others had already been looked at, or the drug wouldn't have made it as far as it did. But the problem is that for a target like CETP, a greasy molecule may be the only thing that'll work. After all, if you're trying to mess up a system for moving cholesteryl esters around, your molecule may have to adopt a when-in-Rome level of polarity. The body may be largely polar, but some of the local environments aren't. The challenge is getting to them.

Comments (19) + TrackBacks (0) | Category: Cardiovascular Disease | Drug Development | Pharmacokinetics | Toxicology


1. DLIB on December 6, 2006 12:53 PM writes...

Well, if the molecules are greasy enough they could/will partition into the lacteal system and they'll see the heart before they see the liver.

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2. Ashutosh on December 6, 2006 4:25 PM writes...

As far as non-selectivity of greasy molecules is concerned, there are exceptions. Taxol is the best example that comes to my mind; it's very greasy and yet exquisitely selective for tubulin.

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3. Jeff on December 6, 2006 5:13 PM writes...

You've just summed up my last 2 years of graduate pharmacology/PK in 5 paragraphs.

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4. Erik Nilsson on December 6, 2006 7:13 PM writes...

Yeah, but Taxol is only adequately soluable to get anywhere at all in the body if it's mixed with ethanol, right?

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5. Daniel Newby on December 6, 2006 8:23 PM writes...

Has anybody ever commercialized a greasy drug dissolved in digestible oil to bypass the liver?

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6. Ryan K. on December 7, 2006 12:11 AM writes...

Ashutosh: I don't think that Taxol is a good example at all. Taxol has low aqueous solubility because it's a brick... not because it's too greasy. It has very low solubility even in organic solvents, basically everything short of DMSO. Also, I'm not sure that "exquisitely selective" is a term I would use for such a highly toxic compound as taxol.

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7. BCP on December 7, 2006 12:20 AM writes...

Ashutosh - the non-selectivity of greasy molecules being discussed here is concerning their ability to distribute widely into different body compartments (membranes, fat stores etc.) - i.e. whatever is not aqueous. But this is normally a non-specific interaction - i.e related to a compounds bulk property. This isn't the same thing as saying that a molecule is not specific for its molecular target. Having said that it's pretty clear that Torcetrapib hits something else other than CETP-- there's been a lot of talk about other CETP inhibitors that do not raise blood pressure, so it seems less likely that CETP inhibition is in itself related to BP increase.

With respect to the previous post, it's certainly ironic that Torcetrapib came from the house of lipinski. It's useful to remember that Pfizer is no stranger to pushing molecules that don't quite obey the rules of one of their more famous former sons. Anyone checked out the logP, no.rotatable bonds and molecular weight of Lipitor recently? (Rule of 5 compliant, it ain't)

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8. Ryan K. on December 7, 2006 6:55 AM writes...

When looking at the structure of Torcetrapib as a synthetic chemist, is anyone else struck with the feeling that it was a very early lead compound that was pushed into the clinic for political and business reasons? (ie-"We need another blockbuster, and we need it quick! Before 2011!") It just has that not quite done yet look to me.

When I first read the patents and process papers, I was kind of confused. Like "This is whats going to save Pfizer?".

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9. Ashutosh on December 7, 2006 10:48 AM writes...

I agree.

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10. Rich on December 7, 2006 2:46 PM writes...

Was the problem strictly with torcetrapib? Or was it the result of Pfizer's insistence that it be a combination drug? When torcetrapib was initially studied and found effective, it was not combined with any other drug.

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11. Pharmachick on December 7, 2006 4:10 PM writes...


What with the recent bad news and all, have you considered teaching Pharmacology or Med Chem?

I have just read this post and also re-capped the earlier posts linked in the first paragraph and I am alternately envious of how well you can get DM across (particularly the Phase I and II stuff) and tempted to commit the cardinal sin by "borrowing" your imagery. Dont worry I'm cursed with a bad case of ethics - no plagiarism here.

But back to my original question, I'm serious about the teaching thing. And you can't beat the job security. Although I'm not sure the ivory tower could afford you.

Re-inspired Pharmachick

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12. Pharmachick on December 7, 2006 4:13 PM writes...

Whoops, thats 4th paragraph. Apparently the ivory tower eliminates ones ability to count too (must be why we settle for the paychecks) :)

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13. BCP on December 8, 2006 12:01 AM writes...

To Ryan K: yes, I had the same puzzled feeling when I first saw the structure of Torcetrapib - there's a brief SAR summary published as part of a review by Sikorski in J Med Chem at the start of the year. There's a little SAR from a poster that seems to indicate that the fluorine content really is important - since the compound they started from was actually a lot more normal looking. Given all the "torcetrapib-prime" structures out there, it's clear that Pfizers template has been effective for others too.

There have also been quite a few elegant mechanism papers published in 06 by pfizer in various biochemical journals which also indicate that Torcetrapib is a pretty specific and effective drug for inhibiting CETP. It's easy to criticize their strategy, but you typically don't make it 2yrs into a huge Phase III if you have terminal PK/ADME problems. This seems like a case of the kind of event that only this sort of trial could uncover, since all other trials were shorter and smaller (with or without atorvastatin on board) and clearly never registered anything like this.

It's been my experience that the minute your molecule meets all the preclinical hurdles that have been set out for you, there's not a whole lot of reason to not push forward into the clinic at full speed - I'm guessing that was what happened with Torcetrapib, it must have been the first one out of the gate.

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14. Dweezil on December 8, 2006 12:51 AM writes...

It's sad to hear about Pfizer's problems. I have fond memories of being an analog-monkey intern back when they were Parke-Davis. If only my advisor could buy me one of those neat characterization robot setups.

I know it's off topic but - why are statins such a big deal anyway? Don't hundreds of people have to take them for every additional year of life expectancy? It seems like a piddly tweak to an aging body to me. Although I just turned 30 and am now starting to wonder when things are going to start going wrong with me, I don't really see the case for taking a drug like that on a daily basis.

One thing that I've never gotten an expert opinion on, but that I am curious about - is there any deep fundamental difference between drugs that target the body's own enzymes and drugs that target the 'other'? For example, antibiotics, antivirals, oncological chemotherapeutics, those all target cells that are 'foreign' in some way. However, many expensive/controversial problem drugs that I've been hearing about lately seem to target the body's own systems. COX-2 inhibitors, statins, anorectics, all notorious for behaving oddly.

Could it be that banging on one enzyme pathway is just an inherently difficult thing to do, and there might be feedback mechanisms that would twist things around even in the event that a designed drug would ONLY hit it's desired target (seems statistically unlikely to me, given the wide variety of active sites out there)? Or are these all isolated issues?

Then again, though, I guess the classic pre-modern drugs of aspirin, opium, cannabis, and foxglove, those are all drugs that target the body's own enzymes, and they're all still in use today in various forms....

but I do wonder, is there some sort of divide here between self-directed and other-directed drugs?

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15. Kay on December 8, 2006 6:47 AM writes...

Some prefer cars with with idiot lights, and some prefer gauges. Lipinski's rules, rotatable bonds, etc. are the idiot lights of this industry. You can bet that there is a medicinal chemist somewhere now rejecting compounds because of rule violations, when rule-violating compounds are what's required. Idiot lights are mortgaging our future.

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16. radmanzulu on December 8, 2006 9:49 AM writes...

The BP elevating problems of torcetrapib surfaced in early Phase 2. The current wisdom of the time is that one of the metabolites inhibited mono amine oxidase. The Groton team felt that it could be managed by lowering the dose and hoped that atorvastatin would also lower BP. Pfizer was running a big study called RESPOND which was evaluating BP lowering effects of atorvastatin at the time.

All the studies are done on top of atorvastatin for two reasons. 1. It is impossible to ethically study patients at risk today without allowing statins. 2. All the financial modeling showed that Pfizer made more money if torcetrapib was not available as a single entity because the real gain was through recapturing the Lipitor business before the 2011 patent extension.

Torcetrapib failed because inhibiting CETP is a flawed strategy. It raises HDL by interfering with its functionality. The majority of cholesterol return to the liver is via ApoB particles and this requires functional transfer from HDL to LDL via CETP. All the RCT studies done by Pfizer, in animals and humans, either failed to show an increase or showed a trend towards worsening RCT and the best they could claim out of them was that "RCT was not worsened". Not too promising for an HDL elevating drug! When that fact came out, the discussion morphed to the other effects of HDL (anti-oxidant, anti-inflammatory, anti-coagulant) but this data was totally lacking for torcetrapib. Early in the program, people like Brian Brewer and Michael Brown warned Pfizer that blocking CETP was likely to accelerate atherosclerosis. Over time, everyone drank the Cool Aid but now the truth is out. It's not the BP, it's the mechanism. While BP is a potent risk factor, the BP elevation with torcetrapib does not explain the magnitude of the disaster. Particularly if you feel that there is a balancing benefit from CETPi.

Future HDL approaches will have to focus on functionality rather than levels of HDL. The next successful drug will likely lower HDL while improving it's functionality and will work via SRB1!

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17. Bernard on December 29, 2006 10:14 AM writes...

Interesting postings here on Torecetrapib. I am one of the 15000 patients in the test group of Pfeiser and was told that I was not a placebo test case but indeed had Torcetrapib for (luckily !) only 9 months. I am a angina pecdtoris patient and after cath. in 2003 the specialist discovered a blockage on a very far artery in the LAD for 70-80 % and was then not able to put a stent in the artery. So I was from then on medication (20 mg Pravastine, 2.5 mg betablocker and bloodthinner 80 mg) Regular ECG tests during cycling over the period of 1 1/2 year showed very good improvements due to medication, reducing weight from 86 kg to 79 kg and better dieet. Then I joined the Pfeizer experiment in phase 3 and replaced Pravastine with the (as it now seems) real Torcetrapib and 20 mg Lipitor. WITHIN 7-8 months (!!) I noticed during daily excercise that my condition decreased and felt out of breath more and more. During earlier check-up at my cardiologist (cycling and ECG) this year it showed that something was wrong. A new cath took place and to the astonishment of the specialist he found that one major artery was blocked in full length and a Seifert stent was placed. Wonder oh wonder how this could happen ! ??? I was put on a higher dosis lipitor (40 mg) but continued with taking in the Torcetrapib. My HDL levels were EXTREMELY low then and during a checkup with Pfeizer I was taken off Torcetrapib since 40 mg Liptor + Torcetrapib was not allowed.

The blockage which was discovered in early 2003 was deblocked by another specialist later this year was done with a polymere stent and my overal spectrum is good at the moment, be it that I am on 80 mg Lipitor right now which indeed has its side effects. (Weakness and muscle pains)

My question is though this: Could the Torecetrapib be the cause of the total artery blockage ? And how long will it take for the artery's to clean up, since I am afraid that all this unnecessary cholesterol may still be present in my body and co9uld even create blockages to the brain etc.? Suppose that Torcetrapib was the cause of all this, without it I would not have the need for a extra stent and would bot have to increase to 80 mg Lipitor, which in my personal opinion is too high, since I was o.k. before using Torcetrapib ? And finaly should I claim for demages with Pfeizer based on earlier ECG tests reports and the sudden problems after 7-8 moth use of Torcetrapib ?

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18. sanaa jummal on May 19, 2011 6:05 AM writes...

In reference to the comment-"failure rate of drugs that have been used for years in human patients already, and already studied under clinical conditions ,is not anything like 90%.Is it zero percent?Has anyone failed yet, taking one of these old medications back to the FDA?Even once?
I would like to ask you, if we were to take Aspirin back to FDA, would it STILL pass the regulatory process, considering the number of side-effects involved.

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19. sanaa jummal on May 19, 2011 6:07 AM writes...

In reference to the comment-"failure rate of drugs that have been used for years in human patients already, and already studied under clinical conditions ,is not anything like 90%.Is it zero percent?Has anyone failed yet, taking one of these old medications back to the FDA?Even once?
I would like to ask you, if we were to take Aspirin back to FDA, would it STILL pass the regulatory process, considering the number of side-effects involved.

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