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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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January 27, 2014

The Nasty Side of HDL

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Posted by Derek

A recurring theme here when I talk about cardiovascular drug discovery is how poorly we understand human lipidology. Surprise after surprise has followed on efforts to lower LDL and/or raise HDL, to the point that a person really has to wonder if the success of the statin drugs was a fluke. (And they could be a fluke in more than one way - perhaps the LDL-lowering effects are, for some reason, more beneficial through that mechanism than they might otherwise be, or as many have speculated, there might be off-target effects that are also helpful).

Everyone seems to agree, though, that raising HDL is (or would be) a good thing. Attempts to do that pharmacologically, though, have come to grief, so the evidence we have is through longitudinal studies and the occasional mutant line with unusually high HDL. Both of those have their pitfalls when it comes to drug targeting - there are, for example, people with HDL-raising mutations that don't see to show any good effect for it.

Now comes this paper in Nature Medicine that identifies an oxidized form of HDL (specifically, ApoA1 protein) in arterial plaques. This modified protein is useless for cholesterol scavenging, exacerbates inflammation, and impairs biogenesis of normal HDL. This makes it a good candidate as a diagnostic marker (which is where the paper is aimed, rightly), and also a good candidate for anyone working on HDL-raising ideas to keep an eye on.

Merck, for example, is pushing ahead with their CETP inhibitor compound anacetrapib Last report I saw on that one was on some rather alarming pharmacokinetics - the drug appears to take a long time to wash out. Long, as in "still detectable several years after the last dose". Given that it looks like something that could be used to line a nonstick frying pan (like most of the other CETP compounds), that's quite believable. As late as Merck is in the clinic, they're not going to be able to jump in and start looking for this new oxidized HDL form so easily. But it would be something to think about

Comments (13) + TrackBacks (0) | Category: Cardiovascular Disease


1. anon on January 27, 2014 10:25 AM writes...

If "still detectable......." means in plasma, then it is very surprising that anacetrapib has such persistence given it has a metabolic hotspot (an aromatic methoxy).

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2. Anonymous on January 27, 2014 11:09 AM writes...

My God, with all of those fluoro groups, it a simple depo (lipid deposition/slow elution)effect. As a former MRL scientist, in the old days,(80's to 90') something like this would NEVER see light of a safety assessment candidate. This solidifies my and many other sane scientists that Merck's research train has derailed somewhere between Mumbai and Singapore.

PS Anybody wanna make Book on its calculated vs actual LogP? Mine is >8.

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3. Anon8 on January 27, 2014 12:12 PM writes...

As a former ex-Merck myself, I agree with you. In my time there we started off by placing single "fluoro" group at an ideal location, so as to increase its PK for an ideal, once a day dosing. It was during the later stages of my tenure there that medicinal chemists started to play with one too many trifluoromethyl group making anacetrapib durable to last for weeks as we understand from the clinical trials. I still have my doubts if this CETP analog is going to see the light of the day.

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4. Fluorine on January 27, 2014 12:53 PM writes...

Despite my love for anything that's fluorinated, these compounds look much more like agrochemicals than anything designed for humans. If they persist in the body for weeks how long would it take for nature to decompose these monsters from waste waters???

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5. Felix on January 27, 2014 1:11 PM writes...

I think the actual point about lipoproteins is that they are bad when they are oxidized, and that they fulfill important biological functions when they are not (independent of whether they have high or low density). I really don't think we should mess with such a central molecule as cholesterol (which is contained in all cell membranes and the basis for a number of hormones), when as you said we "poorly understand human lipology".

and of course there are people who collected a lot of evidence against the general use of statins, for example

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6. dearieme on January 27, 2014 1:22 PM writes...

"how poorly we understand human lipidology": and yet some people felt able to instruct other people to eschew eggs yolks, or milk, or whatever, or to take pills with nasty adverse side effects but rather modest potential advantages, all to fight off a medical problem that was anyway in steep decline among the population. This will not be seen as one of medicine's finest achievements.

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7. ProteinChemist on January 27, 2014 9:40 PM writes...

I have to disagree with #5 in principle, since atherosclerosis is pretty darn prevalent. Still, that article makes me sad...

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9. Curious Wavefunction on January 28, 2014 9:32 AM writes...

Given that it looks like something that could be used to line a nonstick frying pan…

So now technically it's out of the frying pan and into the fire?

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10. ProteinChemist on January 28, 2014 3:30 PM writes...

If we're going to throw numbers and links around, the decrease in deaths due to MI (sudden cardiac events) may be falling, but the overall deaths due to heart failure is rising. You could make a significant argument that the increase in MI survivability is due to better understanding of the acute ischemic and inflammatory process along with increased ability to intervene.

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11. dearieme on January 28, 2014 4:34 PM writes...

"If we're going to throw numbers and links around": so vulgar, evidence.

"You could make a significant argument…": not until you explain the rising part of the curve.

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12. ProteinChemist on January 29, 2014 8:14 AM writes...

@11: In a 2008 summary, studies in the US and Europe have estimated ~40-50% of the decline you noted is due to risk factor modification (smoking, HTN, etc), while another 40-50% is due to advances in critical care treatments and methods. As for the rise in incidence, the major attributed causes are lifestyle (smoking, hypertension, etc) with increased life expectancy, though data from earlier in the 1900s, unsurprisingly, are scarce. The link in my earlier post was to a graph showing that overall heart disease and its morbidities are rising, even if one specific cause of death within the spectrum of heart failure is not.

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13. KN on February 1, 2014 8:57 PM writes...

Most of the HDL measured is a fairly large particle (HDL2)that has probably picked up all the cholesterol that it is going to and simply serves as a marker for something that happened earlier in the pathway. Most efforts to raise HDL only raise levels of this marker.

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