Terra Sigillata finds the right chemistry at CENtral Science

Update your bookmarks and RSS feeds

Come to our new home at CENtral Science:

cenblog.org/terra-sigillata

CENtral Science is the blog presence of the weekly ACS magazine, Chemical & Engineering News

Well, as I’ve been alluding to, I’ve decided to leave this state of indie blog purgatory and join CENtral Science, the blog platform of the American Chemical Society’s Chemical and Engineering News.

C&EN is a weekly publication of the American Chemical Society, the world’s largest scientific society that counts 161,000 members across chemistry-related disciplines. Their blog, C&ENtral Science was retooled last March to establish seven blogs written by several C&EN editors and staff writers.

The CENtral Science blogs and their descriptions are as follows:

Cleantech Chemistry by Melody Voith with Alex Tullo

The Cleantech Chemistry blog will take a close look at the business and technology strategies of a number of companies – many of them new – that hope to serve the world’s need for renewable energy, sustainable agriculture, clean water, and non-polluting manufacturing and transportation, among other cleantech sectors.

Just Another Electron Pusher by Leigh Krietsch Boerner

Just Another Electron Pusher will keep you informed about non-traditional careers in chemistry. Here we talk to people who’ve pursued professions away from the bench about what they do and how they got there. We’ll also follow our blogging heroine in her quest for a satisfying job that uses her degree, but doesn’t involve running any %$@& columns.

Newscripts by Lauren Wolf, Bethany Halford, and Rachel Pepling

“Newscripts” is the companion blog to the like-named weekly C&EN column. Here you’ll find even more quirky news nuggets plus videos, polls, and photo galleries.

The Chemical Notebook by Alex Tullo with Melody Voith

The name directly encapsulates what the blog is meant to be. The topic is the chemical industry: those companies such as Dow, ExxonMobil, BASF, and DuPont that are engaged in the chemical transformation of one molecule to another as of part of a manufacturing stream that ultimately results in products suitable for daily use. By “notebook” what is meant is a reporter’s notebook. The blog aims to make use of those interesting tidbits of the sort found in a reporter’s notebook but might not fit neatly in the print edition of C&EN for one reason or another.

The Editors’ Blog by Rudy M. Baum and A. Maureen Vorhi

There’s nothing cute about the name of this blog or its contents. The only thing to note about the title is that “Editors” is plural, as both Rudy M. Baum, C&EN editor-in-chief, and A. Maureen Rouhi, C&EN deputy editor-in-chief, will host it.

The content you can always expect to find here is the current week’s editorial. We hope readers will use the Editors’ Blog to add their own point of view on the topic being discussed in the editorial. We’ll do our best to respond to comments as they come in. Occasionally, we’ll post an additional entry during the week when something of interest comes to our attention.

The Haystack by Lisa Jarvis and Carmen Drahl

C&EN editors Lisa Jarvis and Carmen Drahl weed through pharma’s molecular mountain to pluck out the drug developments worth noting. Coverage spans science and business context for drug industry news; spotlights on academic and industry conferences; interview outtakes and updates from drug discovery features in C&EN’s pages; and the employment prospects for chemists working in life sciences.

The Safety Zone by Jyllian Kemsley and Jeff Johnson

The Safety Zone covers chemical safety issues in academic and industrial research labs and in manufacturing. The blog is a place for exchange and discussion of lab and plant safety and accident information without the fanfare of a news article. The lead writers are C&EN associate editor Jyllian Kemsley and senior correspondent Jeff Johnson. The blog also includes contributions from other C&EN staff writers as well as health and safety experts in academia, corporations, and government.

I’m delighted to join this fantastic group of writers and will focus on the chemistry aspects of natural products – from prescription and OTC drugs to herbal and non-botanical supplements.

My initial welcome post at the CENtral Science home of Terra Sigillata provides the backstory on my move to my chemistry roots.

I apologize for moving again about a month after leaving ScienceBlogs but I’m grateful that you chose to follow me here. I hope that you’ll join me over at CENtral Science.

These are interesting times. The diaspora from ScienceBlogs and mergers with indie bloggers has brought together new partnerships, such as Scientopia, and strengthened existing ones, such as Lab Spaces.

To help you keep track of these networks, Dave Munger, Anton Zuiker, and Bora Zivokvic launched this week an aggregator of science blogging networks called – no surprise – scienceblogging.org. Many thanks to these fine North Carolina gents for including CENtral Science among their featured networks.

The discerning science connoisseur have more and more choices out there and we appreciate your readership. The next time your leisure reading calls for a science blog, I hope that you’ll consider joining us at CENtral Science, the new home of Terra Sigillata.

Update your bookmarks and RSS feeds

Come to our new home at CENtral Science:

cenblog.org/terra-sigillata

How to promote a science blogging network at a national scientific meeting

Bora Zivkovic, DrugMonkey, and I have been really impressed by this idea by the online folks over at the American Chemical Society’s Chemical & Engineering News. This week, their blog network, CENtral Science, has been promoting their presence at the upcoming national ACS meeting in Boston.

Folks may not know this but ACS is the largest professional scientific society in the world with 161,000 members.

DrugMonkey, the king of science blogging schwag, has previously mentioned the benefits of such a promotion several times to another science blogging network but it never got traction with the powers-that-be.  But here’s the idea from CENtral Science – from this post:

<start>

Here’s how to win:

  • Six key words will be hidden among the blogs between August 15–22
  • Collect all six key words and bring them to the C&EN booth #527
  • Pick up your FREE CENtral Science t-shirt*
  • Wear your t-shirt in the exposition hall Monday and Tuesday and you might be selected by C&EN staff to receive one of the VISA gift cards (worth up to $50) given out every half hour

*While supplies last

CONTEST RULES: This promotion is ONLY valid from 8/15 to 8/24. A total of 350 t-shirts will be given out (one per person) from 9:00 a.m. through 5:00 p.m. on 8/23 and 8/24 at booth #527 in the expo hall only. To receive a t-shirt each individual must present all 6 (correct) key words. Winners must be ACS members to participate. ACS staff and their families are not eligible. All gift card recipients must be wearing a CENtral Science t-shirt. There is no guarantee of winning any prize. Gift card winners will be chosen at random every half hour during published expo times.

<end>

Now THAT’s how you do it.

You have to read the blogs to pick up each of the six keywords.

Three hundred and fifty T-shirts. 350!

And you wear them at the meeting.

And they give away a $50 $10, $25, or $50 gift cards every half hour for two days.

The T-shirt is very nice, by the way, and I’m grateful to C&EN Online editor, Rachel Pepling (Twitter) for sending me one. I will be wearing it for our panel discussion on Tuesday! Rachel’s also a Gator so she gets even more favor points from me.

Once again, hunt me down in Boston if you’d like to say hello.  I’ll be the one in the yellow CENtral Science T-shirt.

Metamorphosis

Warning: rare self-indulgent post.

Blogging has been and will be light over the next few days while we are packing up things around here to move to our next, more permanent home.

In the meantime, you may have noticed here and on Twitter that part of my big news is that I will begin writing under my PharmMom-given name.

My dilemma has been that I have two Twitter accounts. @AbelPharmboy has been the one I use for all blog-related stuff as well as any other gems of my mind that can fit into 140 characters.  Thanks to you, I have 1,600 followers at that account. However, I also have a real name Twitter account that I used for my now-fledgling-and-almost-nonexistent music career and local banter with folks in the Durham-Chapel Hill area. That one only had 200 followers until I began announcing my metamorphosis.

With the pending blog move and melding of my IRL and online identities, one of my mentors, Twitter follower, writer, editor, and Johns Hopkins journalism professor, Mary Knudson, asked what I was going to do regarding the two avatars I use for each Twitter account.

One of my dear friends was enthusiastic about me coming up with a new avatar for the real name account but I’ve been worried about losing old followers who might not recognize the real name avatar.

But coming to the rescue from across the pond is my devoted reader and neuropharmacology enthusiast, Synchronium – world-famous for showing not one but both nipples in the British press.

Here is my metamorphosis:

Follow me now @davidkroll on Twitter.

More news on our move as it becomes available.

Lunch-and-Learn with us next week in Boston at the American Chemical Society meeting

I'll get to meet one of my heroes. Image courtesy of Pharmagossip.

I’m really excited to be going up to Boston for a few days next week to attend the fall meeting of the American Chemical Society.

Besides presenting some of our collaborative work, the highlight of my time there will be with Carmen Drahl of C&EN and The Haystack blog hosting a panel on chemistry and pharmaceutical blogging. The session will be held 12 noon – 2 pm on Tuesday, August 24 with Derek Lowe (In the Pipeline), Ed Silverman (Pharmalot), Michael Tarselli at Scripps Florida, and your humble correspondent.

Here’s a PDF with more details. Fellow Haystack blogger and C&EN Senior Editor, Lisa Jarvis, will be livetweeting the session. So be sure to follow Lisa @lisamjarvis.

Here’s the description from Carmen:

These folks will each give a short talk, but the real highlight here is the panel. I’d love for people to show up with great questions. Want to talk about how blogs are playing a role in discussing layoffs and employment? How about the trickiness to promoting new drugs on the web? Or what role new media should have in critiquing papers? The panel’s as good a time as any to bring those issues up.

I’ll be moderating the event, which is slated for Tuesday, August 24, from 12 noon till 2PM in the Boston Convention Center, Ballroom West.

It costs $16 to sign up for the session, which includes lunch. You can register for the event at the main ACS meeting registration site here. It is listed as the MEDI Lunch and Learn/Ticket No. SE 19.

Get more information about the event from this promo flyer.

I’ll be honest with you folks – I’m peeing my pants with anticipation.

Derek Lowe is the grand master of pharma blogging. Derek is a medicinal chemist who has somehow managed to write from the standpoint of a pharmaceutical industrial chemist and give us insights that you’ll rarely find elsewhere in the blogosphere. In fact, it was an interview with Derek in The Scientist in August 2005 that led me to start this blog. Derek does us a great service in academia by helping our trainees learn what it’s like to work inside a drug company, a place that about half of my trainees and fellow Ph.D. students now work. The 52 posts in his “Academia vs. Industry” category is a great place to start reading.

Ed Silverman is the go-to writer for coverage of the pharmaceutical industry, at least on this side of the pond (hello, Pharmagossip!). I respect a lot of other pro writers and bloggers on that beat such as Matthew Herper at Forbes and Scott Hensley when he was at the Wall Street Journal Health Blog, but now editor of NPR’s Shots health blog.

But Ed wrote for many years at the newspaper of my childhood, the Newark Star-Ledger, at a time when I dreamed of working for a northern New Jersey pharmaceutical company. With 75% of US pharmaceutical companies having a presence within 150 miles of Newark, Ed was at the heart of the business and told it like it is.  In the new home of Pharmalot with Canon Communications, he continues to provide cutting edge news on the drug industry and current legal actions in the community. Ed’s off on summer break right now but will return in time for our talks and panel discussions.

I haven’t met Michael Tarselli yet but I’m excited to do so and learn about the Scripps presence in Jupiter, Florida, where I have a few old colleagues. I’ve already been fortunate to meet Carmen, a Princeton-trained PhD chemist-turned journalist – Bora Zivkovic has a nice interview with her from ScienceOnline2010.

For those of you who won’t be there, Carmen is asking folks to send in questions for the panel via this survey form.

I want to ask Derek how in the heck he got the okay to blog from the highly risk-averse environment of a pharmaceutical company and how he approached this when a plant closure required that he find another position. Did his blogging help him drum up prospects and did his ultimate employer view his visibility as a blogger as a plus?

And in the wake of the Pepsigate exodus from ScienceBlogs, what is the place for writing about being a scientist in industry without being a pawn of one’s employer? I think that it’s essential for there to be just as much blogging by industry scientists as by academics and professional science writers. In chemistry, it seems to be much more accepted that one will work in a corporation (my data-free impression only). But our fellow scientists trained in pharmacology, genetics, or molecular biology have just as much opportunity to work in industry, large and small. Why aren’t we doing more in the blogosphere to prepare our trainees for these opportunities?

What would you like to see discussed at this panel? Drop a line in the comments or go over to Carmen’s response page.

And if you’re in Boston, please come say hello!

K2 Spice associated with death of young Indiana mother of two

Welcome to readers arriving via Adam Brown’s referral from Cracked.com. I’ve since moved my blog where I have written extensively on the fake weed phenomenon over the last year-and-a-half.

Click here to read my compilation of synthetic marijuana posts at the new home of this blog.
 


 

From the overnight e-mail referrals of PharmGirl, MD, whose insomnia fuels much of my blogging, comes a story from Middletown, Indiana, on the death of a 28-year-old woman from smoking a synthetic marijuana product.

From WXIN-TV in Indianapolis:

A mother of two is dead after using a synthetic-marijuana laced incense known as “Spice.”

Now her friends and family want the drug outlawed since more and more people appear to be dying from it.

“Yesterday I lost one of the most important people in my life,” says Heather Hogan, blinking back tears, still trying to make sense of a life taken so suddenly.

A common brand of "herbal incense" or "synthetic marijuana."

Several “herbal incense” products sold as K2 or Spice (usually Spice Gold) have permeated the media over the last year, in the US at least, as legal alternatives to marijuana. These products contain one or more synthetic chemicals designed to bind the same cannabinoid receptors in the brain as those affected by the active compounds in marijuana.  These synthetic compounds, called cannabimimetics, do not have the same chemical structure as marijuana’s THC but still have equal or greater potency and effectiveness. Most recognized among these chemicals is JWH-018, so named by the research team of Clemson University professor emeritus, John W. Huffman, who worked on these molecules as biological probes in the mid-1990s together with some of the best behavioral pharmacologists in the US.

For more reading, go to these posts by us, DrugMonkey, and Dr. Leigh.

However, if these compounds do indeed behave like those in marijuana, deaths associated with their use might not be expected.  However, there is at least one other Indiana death from May that is associated with Spice use. Unlike the current article, the May case has a statement from the coroner:

“Given that it was reported that the decedent may have used an unknown substance call “K 12 spice”, a synthetic drug being used by some smokers as a legal substitute to marijuana, we will review the toxicology results to determine what chemicals are involved. We know that there are current studies being done to determine the effects of this substance. We will follow this case closely and watch for other related types of unexpected deaths.”

The coroner probably meant K2, not K12. But regardless, could this stuff cause death?

DrugMonkey, Leigh, and I have been monitoring the literature and our comment threads but most of what we see are from users who report, at worst, some very unpleasant experiences with K2 or Spice use.  However, a couple of our commenters have noted that the products can cause seizures. And if severe enough, a seizure can cause death. (P.S. Leigh has started writing a new blog at Scientopia.org called Neurodynamics.)

This particular commenter of ours who purchased pure JWH-018 to make his own herbal blend reports that while one cannot usually overdose on marijuana, high doses of this compound are very different. Other habitual marijuana users report that some high-dose effects of K2 Spice reported sound similar to those of very strong strains of cannabis.

More and more of these kinds of products are popping up under other names such as Colorado Chronic, Dragon Spice, HUSH, and others.

So, what’s the story here? Let’s assume for a moment that these deaths can be causally linked to synthetic marijuana use.

Could lethal effects of K2 Spice be due to a synthetic contaminant?

My hypothesis is driven by pharmacology/toxicology history. In the early 1980s, young people started showing up in San Francisco hospitals with symptoms of shaking and muscle rigidity that looked just like Parkinson’s disease that usually afflicts folks in the 60s or, in the early-onset version, their 40s. The cases were traced back to an East Coast chemistry graduate student who had been trying to synthesize MPPP an analog of the synthetic opioid drug, meperidine, to prepare a “synthetic heroin.”

In this 1983 Science paper, J William Langston and other colleagues at Stanford identified the presence and activity of a neurotoxic by-product of illicit MPPP syntheses called MPTP. Langston’s group reviewed that case of the Maryland chemistry graduate student who had presented with similar symptoms in 1976 while using this 1947 synthetic scheme, part of a series of four piperidine synthesis papers in that issue of the Journal of Organic Chemistry. Davis et al. reported on this case in 1979 in Psychiatry Research that the student noted the onset of parkinsonian side effects when injecting the compound made after taking some synthetic shortcuts following several successful batches. The student, now known as Barry Kidston, died after a cocaine overdose and his brain slices are those shown in the Davis paper.

Langston’s group later reported in Neuroscience Letters that MPTP is metabolized in the brain of non-human primates to the highly-reactive neurotoxin, MPP+ (interestingly, an equally high ratio of MPP+ to MPTP was observed in the heart but I’ve not read anything about cardiac effects of MPTP). I should also note that the use of non-human primates for this work was critical to understanding how this toxin caused parkinsonism – the effects were not seen in rats given MPTP.

Production of this highly-reactive pyridinium ion was later shown to result form neuronal metabolism by monoamine oxidase B, the same enzyme we normally use to inactivate dopamine. The MPP+ caused selective death of dopamine neurons in the substantia nigra, “comparable in severity to that usually seen in idiopathic parkinsonism.” (Quote from Langston et al, Science 1983; 219:979-80 about Kidston’s pathology)

For more reading on this topic, Langston co-authored a 1995 book entitled, The Case of the Frozen Addicts, that also fueled a NOVA special. A New England Journal of Medicine review of the book appears here.

MPPP, the intended illicit compound, and MPTP, the proneurotoxin that is oxidized in the brain to MPP+.

This remains an active area of research today because environmental causes of parkinsonism may be mediated similar by compounds we encounter daily – in the 1980s, Sol Snyder’s group at Hopkins showed that MPP+ is made in and exported from astrocytes to kill surrounding neurons and just last year another group at Rochester and Columbia showed that identified an organic cation transport protein, oct3, that’s responsible for this export.

In the case of JWH-018 and related compounds, they are not piperidine (a six-membered saturated ring containing nitrogen) but rather indoles, a five-membered nitrogen-containing ring connected to a benzyl ring. Both are heterocycles, meaning they are carbon rings with nitrogen and, like the methyl on the pyridine nitrogen in MPTP, the nitrogen in JWH-018 is modified with an aliphatic group (a five-carbon pentyl group, in this case).

The cannabimimetic, JWH-018, sold pure and in K2, Spice, and other "synthetic marijuana" or "herbal incense" products.

My question to my chemistry colleagues is whether something could happen in the JWH-018 synthesis to create a situation on the indole that could allow this to be activated to a reactive cation. I’m not sure how the carbonyl electrons one carbon off from the indole might influence things. But then again, we have indoles everywhere endogenously – in tryptophan and serotonin.

Just thinking out loud here – although I’m happy to partner with one of my chemistry colleagues to suss this out – but the cases of deaths reported with K2 Spice, if causally associated, seem too sporadic to be a general theme. The fact that these two cases (and perhaps three) in Indiana smells to me like a locally-restricted distribution of a “bad batch.” I anticipate that poison control centers and forensic analytical chemists in Indiana are on the case.

But here’s a case where I really wish I knew chemistry better. But, in true blog tradition, I’d rather open up this discussion to chemists of the blogosphere rather than try and be all secretive and see if this hypothesis can be quietly tested with my colleagues.

I see that some of my chemist friends have followed me over here from the old digs at ScienceBlogs – what say you, o learned ones?

Sustained interest in K2 Spice, JWH-018, and related currently-legal cannabimimetic products

Just a quick post this morning as I am performing my professional responsibility to our nation’s health research agency.
In yesterday’s issue of USA Today (which I only read on the iPhone app or when staying at a hotel that gives it to us free), Donna Leinwand wrote about a currently legal substitute for marijuana called by various names such as K2, Spice, Black Mamba.

Nearly a dozen states and several cities are banning or debating bans on K2 — a packet of herbs coated with a synthetic chemical that mimics a marijuana high when it’s smoked — amid fears that its use is spreading among young people.

Each of these products is comprised of a generic plant material fortified with one of more marijuana mimics, or cannabimimetics, originally synthesized in the 1990s by Clemson University organic chemist John W. Huffman and his graduate students. These compounds generally go by JWH followed by the lab’s code number for the compound. The most popular of these is JWH-018.
These compounds are not considered cannabinoids since they are synthetic and do not bear obvious structural similarity to Δ9THC or other naturally-occurring cannabinoids. However, these compounds do bind cannabinoid receptors in the brain and appear to produce psychoactive effects similar to that of marijuana. Descriptions of various K2 Spice products, and now pure JWH compounds that have become available, are richly described by our commenters to the February post. In fact, a comment received this week, speaks of the risks of the variable levels of JWH compounds that might be sprayed on different products.
The primary driver of K2 use appear to be by cannabis enthusiasts who are either on probation or otherwise subject to urinary drug screening tests that detect THC but not (yet) the JWH compounds. Others simply wish to purchase a still-legal high rather than risk the variable ire of law enforcement officials around the US.
For much more on the pharmacology and risks of dependence on K2 or pure JWH-018, you can read two posts written under the ScienceBlogs masthead in February, one by me and one by my blog brother, DrugMonkey.
Brother Drug and I have been completely blown away by the sustained interest in each of our posts that has actually grown over the last 100 days. In both of our cases, approximately 50% of our readership lands on our February K2 posts. Perhaps this is no surprise given that each of our posts show up at the top, or at least the first page, of Google search results for “K2 Spice.” On top of this, I was the beneficiary yesterday of Reddit member Travesura who recommended his followers to us with the teaser:

“Heard of that “K2 Spice” that everyone has their shorts in a wad over? Here is the best explanation that I have seen about what it is, and how it works.”

Thanks to Travesura and the timeliness of Leinwand’s USA Today article, our February K2 Spice was the landing site of 2,853 of our last 4,000 visitors.
Holy moly.
But I learned possibly of another trend: we received a fair number of hits yesterday from various US military IP addresses, some coming via search terms involving detection of JWH-018.
For our military readers, has any directive come down the pike that soldiers will now be screened for JWH-018 use? Or is this just a coincidence?
But I still have no explanation as to why both DrugMonkey and I are getting such sustained interest in this topic, even more than for previous posts that had short-term high readership such as herbal products adulterated with erectile dysfunction drugs and the Evolv water/M.D. Anderson kerfuffle.
Update: The always-excellent Erowid site has information on the approach to K2 Spice by the US military. The US Army has banned the substance and this January 23, 2010 article by Hope Hodge at the Jacksonville (NC) Daily News on the possible discharge of two Marines at Camp Lejune:

Marine Corps officials did not immediately respond to queries about working policies surrounding spice or how Marines aboard Camp Lejeune are briefed about it. Base officials said that, in place of specific guidance, the use of spice is illegal under SecNav Instruction 5300.28d and OpNav Instruction 5350.4c, which broadly regard substance abuse prevention and control.

Hodge followed up on February 5 with a report that the US Marines has issued a ban of 10 substances that include Spice and Salvia divinorum, the source of the disturbing hallucinogen, salvinorin A.

Sir James Black (1924-2010) – Physician, Pharmacologist, Gentleman

Have you ever taken one of the now-over-the-counter heartburn relief remedies like Tagamet, Zantac, or Pepcid?
How about the beta-blocker atenolol (Tenormin) or metoprolol (Lopressor) for antihypertensive therapy, or the original less-selective beta-blocker propranolol (Inderal) for migraines, presentation anxiety or stage fright?
Sir James Black - David Levenson Rex Features.jpgIf you answered yes to either question, you owe a debt of gratitude to Sir James Black, the Scottish physician who left us earlier this week at age 85. The best obituary I have seen memorializing Sir James comes from the UK Telegraph.

Black was called the father of analytical pharmacology and was said to have relieved more human suffering than thousands of doctors could have done in careers spent at the bedside. Certainly, no man on earth earned more for the international pharmaceutical industry.
Yet though he became joint winner of the Nobel Prize for Medicine in 1988, Black derived little personal financial benefit from his discoveries. Among businessmen he had a reputation as an irascible maverick and this prickly independence, combined with an antipathy to big institutions, led him to flounce out of jobs whenever he felt corporate short-sightedness was getting in the way of research.

Others can be read at The Independent, The Times, The Guardian, The Scotsman, and BBC News.
It is rare for a scientist to discover one drug that makes it to market. Sir James not only led the discovery of two major drugs, propranolol and cimetidine. As if that were not enough, each drug was a “first-in-class” agent, the first approved drug that acts via a novel mechanism of action.

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Icariin from horny goat weed is structurally unrelated to sildenafil (Viagra®)

In our last post, we discussed a recent USPTO ruling that rejected a claim of the Pfizer patent on the erectile dysfunction drug, sildenafil (Viagra®), to a novel oral treatment for the disorder. The patent appeals panel ruled that the existence of horny goat weed, a traditional Chinese medicine used orally for impotence, was grounds for rejection of the claim.
Frequent commenter daedalus4u pulled out US Patent #6,469,012 (filed Mar 4 1996, issued Oct 22 2002) wherein the relevant claim 24 reads:

A method of treating erectile dysfunction in a male human, comprising orally administering to a male human in need of such treatment an effective amount of a selective cGMP PDE inhibitor, or a pharmaceutically acceptable salt thereof, of a pharmaceutical composition containing either entity.

The claim should never have been allowed in the first place, said daedalus4u, and if upheld would have allowed Pfizer to block sales of horny goat weed. I’m also assuming that upholding claim 24 would have also allowed Pfizer to block sales of follow-on PDE5 inhibitors such as Lilly’s Cialis®. But again, I’m not a patent attorney so I welcome further discussion on this point.
We also heard from my dear old colleague from Adelaide, Professor Ian Musgave. Ian is a pharmacologist who is probably better known in the blogosphere for his astronomy expertise (Astroblog, Southern Sky Watch, and contributing editor to Sky & Space).
But Ian is first and foremost a pharmacologist and raised this point:

Wait a minute, let me get this straight. The patent on Sildenafil, a compound that was rationally designed to specifically inhibit PDE (1) and developed prior to 1996 was invalidated because of a structurally unrelated component of a herbal extract that wasn’t even shown to act on the cGMP/NO system before 2001? (2)

Pfizer is supposed to have time travel? The fact that a herbal treatment alleged to help sexual function would turn out, 5 years after the sildenafil patent had been granted (and the concept of PDE5 inhibitors as treatment for erectile dysfunction wide spread) to have effects on PDE5 could not possibly count as prior art. If so, the 1983 demonstration that the PDE inhibitor papaverine could produce erections would have invalidated the sildenafil patent.

The patent boards ruling is patently rubbish. How can sildenafil “logically flow” from a compound that wasn’t even known to really work, let alone known to inhibit PDE?

(1)Nicholas K. Terrett, Andrew S. Bell, David Brown and Peter Ellis. Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction. Bioorganic & Medicinal Chemistry Letters
Volume 6, Issue 15, 6 August 1996, Pages 1819-1824
(2)Xin ZC. Kim EK, Tian ZJ, Lin GT, Guo YL. Icariin on relaxation of corpus cavernosm smooth muscle. Chin Sci Bulle 2001; 46: 485-9.

Prof Musgrave is indeed correct in the argument but daedalus4u points out the ruling did not invalidate the Pfizer patent, just the single claim to the pharmaceutical indication.
So that makes more sense to me and now I think I understand.
But in the discussion, Ian gave us another gem in response to a commenter who argued there was a structural resemblance between sildenafil and icariin, the active flavonol glycoside constituent of horny goat weed:

No, not at all. You can stick the benzofuran of the flavonol on top of the methylxanthine moiety of the sildenafil, but the charge distribution and 3D structure is all wrong, the flavonol has these huge sugar moieties which have the wrong charge and stick out in places that should inhibit binding, it lacks the bulky positively charged ring that fits into the PDE5 specific binding pocket. (I have the an image of the 3D structural overlay if anyone want to see them).
Looking at it, icariin does not scream either methylxanthine mimetic or “PDE inhibitor”, in fact I would guess it would be worthless. However, flavonols and flavinoids have a habit of doing things we don’t expect, such as resveratrol being a very decent cannaboid receptor anatgonist, despite looking nothing like cannabinoids of the synthetic antagonists.

In fact, Ian was kind enough to send us two molecular modeling images of the two compounds which I failed to get posted last night that illustrate the vast difference between sildenafil and icariin. This overlay image was generated with RASMOL, with icariin in the wireframe format and sildenafil in stick format:

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Interview with Dr Ada Yonath, a 2009 Nobel Laureate in Chemistry

Last week in Stockholm (and Oslo), the 2009 Nobel Prize winners were gloriously hosted while giving their lectures and receiving their medals and diplomas. In Chemistry this year, the Nobel was shared by Venkatraman Ramakrishnan, Thomas A Steitz, and Ada E Yonath for their studies on the structure and function of the ribosome, a remarkable nucleoprotein complex that catalyzes the rapid, coordinated formation of peptide bonds as instructed by messenger RNA. My post on the day of the announcement in October was designed to counter the inevitable (and now realized) criticisms that the prize was not for “real” chemistry.
Thumbnail image for BallE09_5253g.jpgOnly ten days later, we in the NC Research Triangle area were very fortunate to host Dr Yonath at the North Carolina Biotechnology Center for the Symposium on RNA Biology VIII, sponsored by The RNA Society of North Carolina.
Among the many noteworthy speakers was Dr Greg Hannon from Cold Spring Harbor Laboratory, a scientist who some feel was overlooked for the 2006 Nobel Prize in Medicine or Physiology, one where Andrew Fire and Craig Mello were recognized for RNA interference and gene silencing.
NC Biotech’s Senior Director of Corporate Communication, Robin Deacle, kindly invited me to an audience with Dr Yonath and two science reporters following Dr Yonath’s lecture. As you might suspect, I was quite honored to visit for awhile with the woman who defied the naysayers and successfully crystallized a bacterial ribosome, then used X-ray crystallography to determine its structure below three angstroms resolution. The fact that she also used natural product antibiotics to stabilize ribosomal structure added to my magnitude of admiration.

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Venkatraman Ramakrishnan, Thomas Steitz, and Ada Yonath win 2009 Nobel Prize in Chemistry

Welcome visitors coming from a recommendation by Dr Carmen Drahl at CENtral Science, the blog of the American Chemical Society’s Chemical & Engineering News (C&EN):

Terra Sig has a fantastic post about the chemistry prize. The money quote: “If I see electrons being pushed around, it’s chemistry.”

Thank you for the kind words, Dr Drahl. New readers, feel free to weigh in down in the comments as to your take on this year’s Chemistry prize.


The 2009 Nobel Prize in Chemistry has been awarded to three amazing scientists who elucidated the chemical bond-by-chemical bond action of the cell’s protein synthesis organelle, the ribosome. Each of the three laureates employed three-dimensional, X-ray crystallographic structures and naturally-occurring antibiotics to dissect the mysteries of the ribosome, making tremendous advances in our knowledge on the least understood process of the central dogma of molecular biology: protein synthesis.

Yes, friends: this year’s Nobel Prize in Chemistry would not have been possible without the awesome power of natural products and the contributions of my natural products chemistry colleagues who provided Ramakrishnan, Steitz, and Yonath with the chemical tools for their work.

Literally dozens of these antibiotics are used clinically around the world and I guarantee that if you possess the relative wealth to have an internet connection to read this, you have taken at least one of these antibiotics.

Tetracycline? Check. Erythromycin or azithromycin? Check.

The scientific background on the 2009 Nobel Prize in Chemistry (PDF) is, as always, the best place for advanced students to start reading about the context of the scientific achievements of the three laureates. These are terrific, underappreciated, and meticulously constructed review articles, and this one by Måns Ehrenberg is no exception. Page 14, for example, provides a detailed list of the antibiotics that target the small and large ribosomal subunits of bacteria.

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