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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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June 29, 2012

The CETP Rogues Gallery

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Posted by Derek

Has there ever been a less structurally appealing class of drugs than the cholesteryl ester transfer protein (CETP) inhibitors? Just look at that bunch. From left to right, that's Pfizer's torcetrapib (which famously was the first to crash and burn back in 2006), Roche's dalcetrapib (which was pulled earlier this year from the clinic, a contributing factor to the company's huge recent site closure), Merck's anacetrapib (which is forging on in Phase III), Lilly's evacetrapib (which when last heard from was also on track to go into Phase III), and a compound from Bristol-Myers Squibb, recently published, which must be at least close to their clinical candidate BMS-795311.


Man, is that ever an ugly-looking group of compounds. They look like fire retardants, or something you'd put in marine paint formulations to keep barnacles from sticking to the hull. Every one of them is wildly hydrophobic, most are heavy on aromatic rings, and on what other occasion did you ever see nine or ten fluorines on one drug molecule? But, as you would figure, this is what the binding site of CETP likes, and this is what the combined medicinal chemistry talents of some of the biggest drug companies in the world have been driven to. You can be sure that they didn't like it, but the nice-looking compounds don't inhibit CETP.

Will any of these fancy fluorocarbon nanoparticles make it through to the market, just on properties/idiosyncratic toxicity concerns alone? How do their inhibitory mechanisms differ, and what will that mean? Is inhibiting CETP even a good idea in the first place, or are we finding out yet more fascinating details about human lipoprotein handling? Money is being spent, even as you read this, to find out. And how.

Comments (22) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology


1. anchor on June 29, 2012 9:09 AM writes...

Derek: If Teflon had another avatar (i.e. incarnation), this is it!

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2. ralphbon on June 29, 2012 10:34 AM writes...

As best I understand it, inhibiting CETP raises a surrogate marker (HDL cholesterol; HDL-C) of a surrogate marker (HDL particles) of a surrogate marker (cholesterol efflux capacity) of a putative beneficial contributor (reverse cholesterol transport) to a desired outcome (atheroprotection).

Again, as best I understand it, CETP inhibition raises HDL-C by artificially stuffing cholesterol into HDL particles. Whether this actually enhances the processes underlying the epidemiologic association between high HDL-C and lower CV risk is a very, very open question. Certainly, to EXPECT CETP inhibition to be good for people is to prematurely link association with causation.

I've always been dubious about the value of this class of agents. I appreciate now learning that medicinal chemists regard them as ugly.

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3. Hap on June 29, 2012 10:46 AM writes...

Nothing says "I <3 fluorine" better than torcetrapib, anacetrapib, evacetrapib, and that BMS compound. At least some fluorine chemists might have jobs for a little while.

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4. David Formerly Known as a Chemist on June 29, 2012 11:22 AM writes...

The Roche compound looks completely out of place in that gallery. No chirality, no halogens, low MW, something you could synthesize in a high school chemistry lab...their chemists must be ashamed of how pathetically uninteresting their molecule looks! Like showing up to the science fair with a baking soda-vinegar volcano!

Just joking of course, kudos for finding a nice simple structure that made it as far as it did.

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5. pc on June 29, 2012 11:33 AM writes...

We often complained about the herd mentality of the upper management CEO the like as one of the contributing factors for the decline of the industry. Very similar pattern here if you ask me, but this time from the bench ...

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6. Hap on June 29, 2012 11:55 AM writes...

On the other hand, their compound does have a thioester in it, which seems sort of surprising considering the number of native peptide ligation papers - I assume cysteine or amines will deacylate it in vivo. Maybe that's the point, though.

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7. Chemjobber on June 29, 2012 1:44 PM writes...

So we know that torcetrapib had to have its own drug delivery technology -- how did the other highly lipophilic compounds get delivered?

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8. NoDrugsNoJobs on June 29, 2012 3:08 PM writes...

There is an increasing body of evidence indicating that low CETP activity is not cardioprotective. More interesting is that in combination with a statin, a low activity CETP allele results in increased mortality. Here is a link:

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9. MPO Guru on June 29, 2012 4:53 PM writes...

The ugliness of CETP as a class does not surprise me; it is the product of modern drug discovery where HTS and low nanomolar potency rules.

CETP compounds were likely first optimized for potency then other attributes considered (physchem and ADMET properties). If medicinal chemistry teams were challenged to give-up some potency but to find more drug-like candidates, I believe more appealing candidates could be found.

CETP In vitro potency

torcetrapib 23.1 nM
anancetrapid 21.5 nM
evacetrapib 5.5 nM
dalcetrapib 9 nM

Another example of modern drug discovery love affair with potency is represented by 3rd generation P-gp inhibitors from late 1990s and early 2000s. These P-gp inhibitors were horrendous looking, even by CETP standard, but were extremely potent. Unfortunately, none of them were any better at clinically inhibiting P-gp than the 1st generation inhibitors quinidine and cyclosporin, even though their potency was orders of magnitude better. Though quinidine had the least potent IC50 value, it could be delivered orally and achieve the highest unbound concentration relative in vitro IC50.

In vitro P-gp IC50 (nM)
GF120918 (Elacridar) 11
LY335979 (Zosuquidar) 1
OC144-093 (ONT-093) 32
PSC833 (Valspodar) 20
XR9576 (Tariquidar) 16
quinidine 2400

Low nanomolar potency is not a drug-like attribute. In fact, more than 25% of approved oral marketed drugs require unbound plasma concentration in excess of 1 uM for efficacy. Below is a partial list. As long as drug discovery teams aim for extreme potency, I believe they are likely to continue to produce candidates such as the CEPT and P-gp inhibitors.

Oral Drugs with Unbound plasma concentration in excess of 1 uM
Ampicillin, Caffeine, Cefatrizine, Cefetamet, Cefixime, Cefuroxime, Cephalexin, Cephradine, Chlorpropamide, Cimetidine, Ciprofloxacin, Clavulanic Acid, Dapsone, Diazoxide, Disopyramide, Fluconazole, Flucytosine, Fosfomycin, Gabapentin, Ganciclovir, Gatifloxacin, Hydroxyurea, Isoxicam, Lamivudine, Lamotrigine, Levofloxacin, Linezolid, Metformin, Methyldopa, Metronidazole, Miglitol, Moxifloxacin
Nevirapine, Ofloxacin, Pefloxacin, Phenobarbital, Phenoxymethylpenicillin, Probenecid
Procainamide, Quinine, Sotalol, Sulpiride, Tetracycline, Theophylline, Tinidazole, Tocainide, Tolbutamide, Trimethoprim, Valproic Acid

Interesting References:

Finding the sweet spot: the role of nature and nurture in medicinal chemistry

Probing the links between in vitro potency, ADMET and physicochemical parameters

Molecular obesity, potency and other addictions in drug discovery
Med. Chem. Commun., 2011, 2, 355 | 349

Preclinical Predictors of Anticancer Drug Efficacy: Critical Assessment with Emphasis on Whether Nanomolar Potency Should Be Required of Candidate Agents
JPET 341: 578, 2012

Quality by Design in lead optimization: a new strategy to address productivity in drug discovery
Current Opinion in Pharmacology 2011, 11: 520

Hypothesis driven drug design: improving quality and effectiveness of the designmake-test-analyse cycle
Drug Discovery Today Volume 17, Numbers 1/2 January 2012

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10. dvizard on June 29, 2012 5:33 PM writes...

> fancy fluorocarbon nanoparticles
that cracked me up :)

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11. Aleck Alexopoulos on June 30, 2012 3:56 AM writes...

I'm pleased to see that you ask whether CETP inhibition is even a good idea. I'm working (as a side project) on a lipoprotein dynamics computational model (ok it has tons of assumptions and approximations) and my - preliminary - results indicate the CETP inhibition leads to decreased LDL-C, increased HDL-C
increased levels of tissue C.
If I include the decreased feedback control of hepatic C production (due to decreased LDL-C) then the outcome is even worse.
Im sure the Pharma companies will end up suggesting the CETP-inhibitors work best in combination with statins.


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12. barry on June 30, 2012 8:24 AM writes...

Torcetrapib didn't fail to inhibit CETP. Neither did it fail by being too potent. It failed because the clinical cohort taking it died earlier than the controls despite lowered CETP activity and elevated HDL levels.
CETP is still considered an interesting target (outside of Pfizer) because people are betting that its adverse effect on life-expectancy is off-target tox. Of course the chance that two CETP ihibitors will share the same off-target liability goes up as their structural similarities go up. I'd say the Roche cmpd is certainly different enough that we could fairly expect to lose off-target tox (if that is indeed what's going on). Can't say the same for the others. Too many conserved features.

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13. Fred on June 30, 2012 8:52 AM writes...

When I first saw the PFE cmpd, I had some choice thoughts about the quality of med chem in Groton. Then I saw the other CETP leads and saw, at least, that everybody was running in the same pack.

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14. A. Postdoc on June 30, 2012 11:34 AM writes...

So, looking in the PDB, there are no deposited crystal structures with any of these bound. Do they even know where they bind? I was going to write a blog post about the binding site but it appears it may be unknown.

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15. More fluorine instead of cowbell on June 30, 2012 7:56 PM writes...

Seriously, what the heck were the discovery teams for these garrish monstrosities thinking?

How water-soluble are these compounds? Is it really a good idea to administer thioesters in the presence of serum proteins? (Native chemical ligation, anyone?) Oh, and couldn't BMS have made that tertiary stereocenter even more crowded?

Having known people on chemotherapy, cremophor EL is not the most pleasant of excipients...

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16. TX Raven on June 30, 2012 9:22 PM writes...

@9, MPO Guru

"Low nanomolar potency is not a drug-like attribute. In fact, more than 25% of approved oral marketed drugs require unbound plasma concentration in excess of 1 uM for efficacy. "

So, If 75% of drugs have free Ceff below 1 uM, are you recommending to work in the "exception space"?

Plus, look at the daily doses of some of the drugs in your list...several are taken in grams per day!

There is nothing wrong with high affinity drugs, as long as you get there with reasonable pchem properties. That is, IMHO.

TX Raven

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17. BCP on June 30, 2012 11:26 PM writes...

Folks need to remember what compounds CETP is designed to shuttle around - yup, triglycerides and cholesterol esters. If you dig into the lit, look at the crystal structures, it's pretty clear why polarity is not going to be your friend.

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18. BIP on July 2, 2012 8:08 AM writes...

Most of these puppies probably required Hot-melt extrusion or Spray-drying formulations (like Pfizer's torcetrapib) to get any sort of bioavailability.

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19. MPO Guru on July 2, 2012 9:17 AM writes...

@ 16, TX Raven

I agree with your comments. Ideally, teams should avoid working in exception space if possible and there is nothing wrong with high affinity drugs with nice pchem properties. The point I was trying to make is: extreme high affinity compounds with lousy pchem and ADMET properties could be avoided, if teams focused on pchem and ADMET properties from the start and were willing to sacrifice some potency for a better overall molecule. Molecules should be designed to maintain optimal balance of potency, pchem and ADMET properties, always keeping clinical dose in mind. Modern drug candidates tend to have much greater potency, yet worst pchem and ADMET (unbound intrinsic clearance) properties than already approved drugs. All in all, I tend to think modern drug discovery places too much focus low nanomolar potency at the expense pchem and ADMET properties (just my 2 cents). If teams can achieve low nanomolar potency with great pchem and ADMET properties, all the better.

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20. Zoltan on July 2, 2012 3:42 PM writes...

Sorry but where was all this wisdom when these molecules were being proposed, synthesised and candidate selected?

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21. Anonymous on July 2, 2012 4:22 PM writes...

There is also a J&J compound, not (yet?) in clinical trials, again with a large helping of fluorines (ten):

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22. Vlad Konings on July 3, 2012 9:06 AM writes...

"Has there ever been a less structurally appealing class of drugs than the cholesteryl ester transfer protein (CETP) inhibitors?"

I dunno. The one on the left looks a little like a Picasso version of my terrier begging for a treat.

Okay, point conceded.

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