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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: Twitter: Dereklowe

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January 28, 2014

Antivirals: "I Love the Deviousness of It All"

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Posted by Derek

Here's a look at some very interesting research on HIV (and a repurposed compound) that I was unable to comment on here. As for the first line of that post, well, I doubt it, but I like to think of myself as rich in spirit. Or something.

Comments (11) + TrackBacks (0) | Category: Biological News | Infectious Diseases


1. Rhenium on January 28, 2014 1:08 PM writes...

What a mess! Three, no four chiral centres... (Count them, Ah Ah AH!)

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2. A Non Mousse on January 28, 2014 2:13 PM writes...

Perhaps the word is being used in the sense someone uses it when they say "Really? Well, that's rich"...

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3. Guest on January 28, 2014 4:00 PM writes...

I've seen luysii comment in here but didn't realize he had a blog. He has some good reads over there.

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4. Anonymous BMS Researcher on January 28, 2014 7:51 PM writes...

The whole story of HCV and HIV treatments right now is fascinating and important from nearly ll the pesrspectives that come up on this blog -- chemistry, biology, public health, pharmacology, the drug business, etc., etc. Too bad Derek cannot say much about antivirals on his blog because his employers have a number of antivirals on the market or in the pipeline. For similar reasons, I also cannot say much on the subject here, since I work for BMS.

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5. David Borhani on January 28, 2014 9:09 PM writes...

I cannot find published human PK data on VX-765. But, in the 2011 Phase 2a epilepsy trial, patients took 900 mg of VX-765 three times a day --- a large dose consistent with the expected rapid clearance of this class of compounds --- with no statistically significant benefit in seizure reduction. See: Progress report on new antiepileptic drugs: A summary of the Eleventh Eilat Conference (EILAT XI) and Registered VX-765 Clinical Trials.

At any rate, apply some common sense: If VX-765 were a viable human drug, wouldn't Vertex be pushing it forward at full speed in a bevy of anti-inflammatory indications (i.e., it's worth reading some history on ICE/caspase-1 inhibitors)? Conversely, if drug exposure is indeed marginal, how many T-cells will commit HIV-induced suicide each time the drug level falls below some critical efficacious level during the days (and weeks and months and years) the patient must take the drug?

RE chiral centers: it's just an elaborated tripeptide (Tle-Pro-Asp) --- not such a big deal, come on! It's the aldehyde that's the issue [wrt clearance].

Sorry to rain on your millionaire parade, Derek!

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6. luysii on January 29, 2014 10:25 AM writes...

#3 Guest -- thanks !!

#5 David Borhani -- I find it amazing that VX-765 was even considered as an anticonvulsant candidate. It's very hard to get things into the brain -- Google the Blood Brain Barrier -- and the molecular mass of VX-765 is over 350, so they had to use a ton of the stuff to just to get it in.

It should be a lot easier to get VX-765 into lymph nodes, where it is presumably producing its therapeutic effects.

Also, it wasn't Derek's idea that he'd be rich (in things other than spirit), but mine.

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7. David Borhani on January 29, 2014 11:16 AM writes...

But we'd all like to see Derek rich, if only as payback for an excellent blog! ;-)

Lymph nodes: Sure, easier than crossing BBB, but then why isn't VX-765 being pushed in inflammation/immunology?

Instead, we have Regeneron's "IL-1 trap" Arcalyst (rilonacept) for Cryopyrin-Associated Periodic Syndromes (CAPS) (and presumably, off-label, for related IL-1-driven syndromes), or Amgen's IL-1 receptor antagonist Kineret (anakinra), also CAPS, *and* Rheumatoid Arthritis, bit it gets washed out by the kidneys nearly as fast as it's injected.... The target (IL-1) is validated in humans for these variety of immunological/inflammatory diseases, but (non-biologic) caspase-1/ICE inhibitors generally don't have the PK parameters to support their use in the clinic.

Maybe knowing that HIV is a possible target will revitalize efforts to find more drug-like and useful caspase-1/ICE inhibitors? That would be a good thing!

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8. luysii on January 29, 2014 1:09 PM writes...

David Borhani #7

Certainly IL-1 is a downstream effector of pryoptosis. Probably there are many of others. Look at all the things that happen AFTER caspase is activated in apoptosis. So going closer to the source might be more effective.

There are a lot of potential problems with pyroptosis inhibitors -- overwhelming infection comes to mind. I might not be to every organisms. The unusual susceptibility of splenectomized individuals to just some types of infection (meningococcus, pneumococcus and H. influenza) comes to mind.

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9. Rastislavus on January 30, 2014 5:59 AM writes...

#4 Anonymous BMS Researcher - can you recommend sites/blogs where antivirals topis is being discussed. Thank you...

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10. Rastislavus on January 30, 2014 6:00 AM writes...

#4 Anonymous BMS Researcher - can you recommend sites/blogs where antivirals topic is being discussed. Thank you...

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11. Anonymous BMS Researcher on February 2, 2014 6:44 PM writes...

@Rastislavus: I wish I knew of such a site; unfortunately Derek's blog seems to be unique. If only there were another blogger much like Derek except his or her employers didn't work in the virology field. There are some excellent virology blogs, but those are mostly about the basic science. SOME of the story about HCV drugs can be found here:

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