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Category → Making Molecules

The Tail’s The Thing – Alkylamine Ethers and Zafgen’s ZGN-433

While posting about the Zafgen obesity drug candidate yesterday, I was staring at the Markush structure we’d drawn for ZGN-433 when Carmen Drahl sent over a 2008 volume of the World Health Organization International Nonproprietary Names (INN) list, a collection of proposed or recommended non-proprietary names and structures for currently-marketed drugs or drug candidates in clinical trials. I glanced down the list to find beloranib, the common name for ZGN-433, and I realized immediately . . . it had the “tail!”

The “tail” nickname should probably be called an (N,N-dimethylamino)ethyl ether functional group. It’s one of the specific atomic arrangements medicinal chemists tack onto lead molecules to improve potency, resist metabolic oxidation, etc. This is one of the more popular groups, it seems, perhaps what someone in catalysis or biochemistry might call a “privileged structure,” a molecular motif that so perfectly accomplishes a given task that it pops up in many different places.

Marketed drugs that riff on this pharmacophore include: Tamoxifen (breast cancer), Benadryl (aka diphenylhydramine, an antihistamine), Dimazole (antifungal), Amiodarone (antiarrhythmic), Gallamine (muscle relaxant), and Evista (estrogen uptake modulator). In Nefopam (an analgesic), the motif is even found embedded in an 8-membered ring, admittedly not the first thing one might think to synthesize – it’s usually harder to make these “medium-ring” compounds  than their 5- or 6-membered counterparts.

In the case of beloranib, one could imagine three roles for the alkylamine ether group. It could serve as an isostere, a group that mimics the space-filling and electronic properties of another, standing in for amino-alkyl side chains found in bioactive plant metabolites like psilocybin or tryptamine. It might also be useful to increase solubility of the drug, which makes dosing easier and improves the drug’s ability to reach the bloodstream when taken orally (Note: this may not have worked for beloranib, since the drug is currently administered by sub-Q injection). A more likely explanation might be the well-established phenomenon of “tuned” basic nitrogens that hydrogen bond with acidic residues in enzyme active sites, increasing binding free energy (better inhibition) – see this 1982 paper by John Katzenellenbogen (U.Illinois) for basicity tuning in Tamoxifen analogues.

We hope Haystack readers will weigh in on what they think the “tail” is accomplishing for ZGN-433. Yesterday’s Zafgen post has already generated some thoughtful commentary via Twitter from John LaMattina, former Senior Vice President, Pfizer Inc and President, Pfizer Global Research and Development:

John_LaMattina: @lisamjarvis Hard to get excited about a compund that acts by a mystery mech. with epoxide moieties. FDA will justifably want long-term tox.

We here at the Haystack would like to thank Dr. LaMattina for his input.

Remedium Technologies Gets A Grip On Severe Bleeding

Maryland is serious about nurturing startups. Drahl/C&EN

In the last year we’ve covered many up-and-coming drugs for controlling the delicate balance between clotting and bleeding. But what happens when something—an injury or a major surgical procedure—overwhelms that system?

Controlling big bleeds is big business, from the battlefield to the operating room. This Monday, at the American Chemical Society’s Middle Atlantic Regional Meeting (MARM) in College Park, Maryland, I heard from Matthew Dowling, CEO of a startup looking to make its mark in that space. The company is called Remedium Technologies, and it’s developing chemically modified versions of a natural biopolymer to make improved materials for stanching blood flow.

Remedium is one of several companies getting on its feet with help from technology incubation programs the University of Maryland. Representatives from several of those companies, including Dowling, gave talks at a MARM symposium on the science of startups. Look here for the MARM session’s program- it includes other companies in the drug and vaccine space, including Azevan Pharmaceuticals (which C&EN wrote about in 2001 when it was called Serenix), Leukosight, and SD Nanosciences.

The biochemical pathway that regulates clotting can’t support severe injuries that lead to profuse bleeding, Dowling said Monday. While several treatments exist for this kind of severe injury, where sutures might not work to close a wound, they have drawbacks that Dowling thinks Remedium’s technology can address.

The company’s material of choice is chitosan, a biopolymer that can be scavenged from waste shells of shrimp or crabs. Chitosan wound dressings are already on the market, but they become saturated with blood and quit sticking to tissue after about 30 minutes, which can lead to more bleeding. As a bioengineering graduate student at Maryland, Dowling developed an alternative chitosan modified with hydrophobic groups that help it stick to tissues longer. This modified biomolecule is the basis of Remedium’s technology. The company likens the material to Velcro because it is the sum total of weak interactions between hydrophobic groups and tissue that help the material stick around, Dowling explains. Once the wound has had time to heal, the material can be gently peeled away.  The chemical structure of Remedium’s hydrophobic groups is proprietary; Dowling used benzene n-octadecyl tails in graduate school.

The company has two products in development- a modified chitosan “sponge” and a spray-on blood clotting foam. Neither of those products is yet available for purchase. In College Park, Dowling showed a video demonstrating how the modified chitosan makes blood congeal quickly, and how the effect can be reversed by applying alpha-cyclodextrin. In a second video, the sponge is tested on a bleeding pig that’s had a major blood vessel cut open. This presentation is similar to what Dowling gave Monday.

Dowling has been running Remedium full-time since he obtained his doctorate from Maryland in 2010—the company was founded while he was still in graduate school, and several classmates are also in the company’s management. The company has an exclusive license for the chitosan technology from the university, and has four patents pending. It has also won several business competitions, including Oak Ridge National Laboratory’s (ORNL) 2010 Global Venture Challenge. Dowling says the university’s technology incubation resources are what made it possible for him to start a company while still in grad school, from providing office space in a building just off campus, to regular meetings with staffers knowledgeable about navigating the regulatory and funding process.

Guest Post: The Medicinal Chemistry Reaction Cookbook- Packards and DeLoreans

We’d like to welcome the talented SeeArrOh to The Haystack as a guest blogger. A Ph.D. chemist working in industry, you might recognize SeeArrOh from the comment threads of your favorite pharma blogs, from Twitter, or from a recent Chemjobber guest post. SAO also enjoyed the paper on what medicinal chemists actually make that caught Derek Lowe’s eye yesterday. You’ll notice a few similar ideas to Derek’s in SAO’s commentary, but a few different insights as well.

Every so often, it comes up: Is there anything really new in med-chem? Is everything just a re-hash of time-honored reactions, set up with closed eyes to produce yellow oils and white solids? Or are there untapped territories ripe for exploration? Sadly, Doc Brown can’t pull up in his fusion-powered DeLorean to tell us what cancer-curing medicines await us in fifty years, so we went to the literature instead.

As authors of a recent J. Med. Chem ASAP (DOI: 10.1021/jm200187y) muse:

…discussions with other chemists have revealed that many of our drug discovery colleagues outside
the synthetic community perceive our syntheses…[are] predominantly composed of amine deprotections to facilitate amide formation reactions, and Suzuki couplings to produce biaryl derivatives. These “typical” syntheses invariably result in large, flat, achiral derivatives, destined for screening cascades.

Not an author. (Wikimedia Commons/Steve Lipofsky)

Our intrepid British authors Roughley and Jordan – his full name, Allen Michael Jordan, was enough to entice this reader – make a case for a wide variety of possible molecular manipulation. Focusing on the output of three med-chem titans: GSK, Pfizer, and AstraZeneca, and papers from three high-impact journals (JMC, BMC, BMCL), they crunch the numbers on drug discovery synthesis and reveal some expected—and unexpected—results. Given the limited scope, the authors admit right away that their findings might not be comprehensive. But hey, let’s dive into the data anyway!

As a bench chemist, I’ve run my fair share of metal-catalyzed couplings, salt formations, and acetylations, so I fully expected total domination of the list by these “workhorse” reactions.

Was I right? Continue reading →

Finding Out Anesthetics’ Mode Of Action

When I think about how drug discovery has changed in the last 100 years, one of the first things that comes to mind is how much more target-focused the process is. Take aspirin as an example of the earlier model. Researchers didn’t confirm how aspirin worked until John Vane’s landmark 1971 paper, over 70 years since aspirin first hit the market.

Compare that to today’s world of drugmaking, where oftentimes researchers have to validate a target- show that it is connected to a disease and that modifying its activity might help treat that disease- before drug discovery can really get going. We’ve written about this process many times- see this account of the development of Lexicon drug candidate LX1031 for irritable bowel syndrome as an example.

But there’s at least one class of drugs where this target-based philosophy is in its infancy- anesthetic drugs. That’s because researchers are only beginning to understand the molecular basis of anesthesia. So it’s not clear which proteins to target or even whether you’d want a molecule that’s selective for one target.

The New York Times spoke with Harvard anesthesiologist Emery Brown last month about the neurobiology of anesthesia, and how being under actually is more like a coma than going to sleep. Other researchers are trying to understand anesthesia at the molecular level, like chemists Ivan Dmochowski and Bill Dailey, and anesthesiologist Rod Eckenhoff of the University of Pennsylvania. I visited their labs yesterday on a jaunt to Philadelphia. They’re among a small number of research teams building fluorescent or light-reactive versions of the anesthetics used in hospitals every day*, in order to figure out what proteins they interact with and which of those are relevant to inducing anesthesia. They’ve got their work cut out for them- for one thing, the anesthetics that are administered by inhalation, such as isoflurane and sevoflurane, bind to a slew of proteins. But if their efforts pay off, they say they will eventually be able to help chemists build better, safer anesthetics.

After exposure to light, azi-isoflurane reacts with proteins.ACS Chemical Neuroscience

More reading: Molecular targets underlying general anesthesia, NP Franks, Br. J. Pharmacol. 2006, 147, S72.

*by anesthesiologists like the guy I married, in the interest of full disclosure.

Ensemble Hits Macrocycle Milestone

Today, Ensemble Therapeutics announced it has developed experimental drugs with molecular structures containing a large ring, which the company calls Ensemblins, against one of 8 key drug targets laid out in a 2009 agreement with Bristol-Myers Squibb Company (BMS). As a result, the drug development program will be handed off to BMS and Ensemble will receive a milestone payment. Neither the drug target nor the milestone payment amount have been disclosed.

I first became acquainted with Ensemble in 2008, when I wrote about a symposium extolling the potential benefits of compounds containing rings of 12 or more atoms, also known as macrocycles, in drug discovery. Continue reading →

First Time Drug Disclosures at #ACSAnaheim

Medicinal chemists, it’s that time of year once again. Time for the ACS National Meeting, and the accompanying symposium where drug companies reveal the structures of drug candidates in clinical trials for the first time. I’ll be on the ground in Anaheim and will be posting from that session (which lasts from 2PM-5PM Pacific Sunday the 27th) and others. Here is the Anaheim Division of Medicinal Chemistry program (pdf).
And here is the list of disclosures:

  • Discovery and characterization of CEP-26401: A potent, selective histamine H3 receptor inverse agonist: R. Hudkins, Cephalon
  • Discovery of BMS-663068, an HIV attachment inhibitor for the treatment of HIV-1: J. Kadow, Bristol-Myers Squibb
  • Discovery and development of LX1031, a novel serotonin synthesis inhibitor for the treatment of irritable bowel syndrome: A. Main, Lexicon
  • Discovery of MK-0893: A glucagon receptor antagonist for the treatment of type II diabetes: E. Parmee, Merck
  • Discovery of ELND006: A selective γ-secretase inhibitor: G. Probst, Elan

Structures May Not Solve Everything

This week’s C&EN cover story is about how X-ray crystal structures of G-protein coupled receptors (GPCRs) help the hunt for new drugs. GPCRs are already a major target for drugs (if not the most popular drug target), but until recently, researchers knew little about the finer points of their structures.

As I mentioned in that story, those high-resolution protein pictures aren’t a panacea, and they won’t replace established drug-discovery technology so much as complement it. I didn’t have room to flesh out that idea in print, so I’m posting a few researchers’ thoughts on this area here today.

Some scientists thought that GPCR X-ray structures are so far of limited utility for discovering allosteric drugs, a class of GPCR-targeted drugs that can dial activity up or down rather than turning it on or off. Some GPCR-targeted drugs on the market already work this way, such as the HIV medication Maraviroc, and many more are in development. (As an aside, I feel as though every time I attend an ACS meeting talk about GPCRs, the room is packed).

“It’s the chicken and the egg story,” says Robert Lutjens, head of core biology at Addex Pharmaceuticals, which specializes in GPCR drug discovery. To get an X-ray structure of an allosteric molecule binding to a GPCR, which would be useful for developing virtual screens, one would first need to find just the right allosteric molecule—one that stabilizes the GPCR sufficiently to enable it to be crystallized. That’s difficult to do, so powerful biological assays are still critical for finding molecules that act at allosteric sites, Lutjens says. Continue reading →

Syntex Made It Possible, Sic Manebimus in Pace, Or Sexy Man Invents Pill: An Evening With Carl Djerassi

Djerassi (left) and Jacobs chat after the screening. Drahl/C&EN

The toughest part of blogging about a chemist like Carl Djerassi has been figuring out where among C&EN’s blogs the post fits. He’s ended up in The Haystack this time, my reasoning being “this is the inventor of the Pill, for Pete’s sake”, but I could just as easily imagine David musing about the pill’s natural product connections (Mexican yams!) at Terra Sigillata, or myself posting in Newscripts about Djerassi’s announcement on a work-in-progress: a new play called “Insufficiency” about a chemist who is denied tenure. (That’s all I know so far!)

It was pouring in DC last night as I sloshed four blocks north of ACS’s headquarters to the Carnegie Insitution for Science, to meet Djerassi and take in a screening of “Carl Djerassi- My Life”, an homage that follows Djerassi to Vienna, Stanford, and SoHo theaters. After the film, Djerassi and ACS Executive Director Madeleine Jacobs had an “Inside the Actors’ Studio”-style chat. Matt of Sciencegeist couldn’t make it for the evening, and I promised him via Twitter that I’d post if Djerassi said anything interesting. That’s when Chemjobber jumped in:

Chemjobber: @carmendrahl @sciencegeist If?

Touché, CJ. Clearly, as Matt then noted, I’d have to post WHEN Djerassi said interesting stuff, not if. So behold: choice Djerassi quotes from the evening. Continue reading →

What’s Your Solution To Drugs In The Environment?

A guest post by C&EN European Correspondent Sarah Everts

A new paper in PLoS ONE reports some alarming data: Bacteria living in the rivers fed by the waste streams of 90 drug production factories in India have high levels of antibiotic resistance genes. The work, from Joakim Larsson’s group at the University Göteburg, Sweden, was a follow-up to his team’s measurement of fluoroquinolone antibiotic and other active ingredient levels in manufacturing waste streams. In that study, sometimes the drugs turned up at therapeutic concentrations.

The research shows that these low–and not so low–levels of antibiotics waste may be exacerbating microbial resistance to drugs we really can’t afford to do without.

Larsson’s work is also another data point in the steady stream of reports that the drugs we use are causing side effects in the environment, with consequences ranging from feminization of fish to microbial resistance.
So what’s to be done? Mae Wu and Sarah Janssen of the Natural Resources Defense Council recently wrote a snappy, pointed commentary in Environmental Science & Technology that effectively says action on the issue is mostly stalled—or in low gear at best:

Identifying effective and efficient solutions is hampered by the complexity of the problem—multiple sources* contribute, only some of which are regulated, often by multiple federal agencies pursuant to various legal authorities. Furthermore significant data gaps mean that individual sources of contamination point the finger at each other without much substantiation. Advocacy groups, drinking water utilities, and government officials have introduced different initiatives to address this situation resulting in a scattershot of partial solutions rather than an overarching strategy.

I wonder if Wu and Janssen would be encouraged by an email that popped in to my inbox at around the same time as Larsson’s paper: A call for researchers to suggest, by means of a websurvey, any number of pressing research questions that need answering about pharmaceuticals in the environment.

The survey is being sponsored by the regulatory agency Health Canada, SETAC pharmaceuticals advisory group and a bit of funding from pharmaceutical companies, but the executors are two researchers at York University in the UK: Alistair Boxall, an environmental chemist who studies drugs in the environment, and Murray Rudd, an environmental economist who has set up similar surveys to prioritize research questions on ecosystem conservation.

So go ahead-visit the survey and have your say.

Rudd says he’s expecting several hundred questions from the survey which will then be whittled down to 40 top priorities at an upcoming Health Canada-sponsored stakeholders retreat in Southern Ontario. These priorities will be disseminated to policymakers, research funders, and the scientific community.

Rudd acknowledges that there’s no guarantee that the priorities will be followed, but he hopes they will provide focus to the community: Something more like an overarching strategy—instead of a scattershot step—to deal with the important issue of pharmaceuticals in the environment.

*Wu and Janssen’s description of how the profile of pharmaceuticals in the environment might be improved by relevant stakeholders is worth repeating. Here’s a précis:
-Chemists could design drugs that have a better end-of-life profile in the environment
-FDA regulators could require more rigorous environmental impact assessments prior to approval
-Environmental regulators could insist that companies completely remove active pharmaceutical ingredients from waste streams
-Doctors could choose to prescribe drugs with a more environmentally friendly profile when the options exist
-Consumers should cease and desist from flushing drugs down the toilet; Those in the agriculture industry should remove antibiotics and growth hormones given to livestock from agricultural waste streams.

Zafgen’s ZGN-433 shows promise for obesity- so what’s it look like?

Just in time to coincide with January’s massive uptick in gym-going, Cambridge, MA startup Zafgen has announced good news about its experimental weight-loss drug for severe obesity. The molecule, ZGN-433, helped a small group of severely obese women (with body mass index of 32-45) lose weight- more so than a placebo. Weight losses varied from person to person, but the midpoints of the range of weight loss results were attention-getting: weight loss of 1 kilogram (2.2 pounds) per week, and 3.1 percent of body weight after 26 days, when the trial concluded. Women taking ZGN-433 in the 24-person study also experienced meaningful changes to their triglyceride levels and levels of LDL cholesterol, the so-called “bad cholesterol”. The news spurred coverage at FierceBiotech, Xconomy, and many other news outlets.

It’s too early to tell whether ZGN-433 will become an FDA-approved weight loss drug. But it’s encouraging to see companies still plugging away at the obesity problem even in light of the challenging year obesity drugs had in 2010. And Zafgen’s announcement today contains some additional tidbits that point interested medicinal chemists toward the kinds of structures Zafgen might be working on.

When we last covered Zafgen, the company had revealed the target of its experimental drugs, methionine aminopeptidase 2. And we learned that in animal studies, Zafgen was using a naturally-occurring molecule as a methionine aminopeptidase 2 blocker- fumagillin, or ZGN-201 in the company’s parlance. We knew Zafgen was using another molecule in human trials (that’s ZGN-433), but at the time the company didn’t disclose the molecule’s structure, or the name of the company they licensed the molecule from.

In today’s announcement, Zafgen unveiled that company’s name: ZGN-433 was initially developed at Korea’s Chong Kun Dang (CKD) Pharmaceuticals. So I decided to perform a Google Patents search to see what kind of structures CKD has patented. My very cursory search revealed four patents but as you can see below, some of the sample structures in the patents differ quite a bit from fumagillin. Zafgen’s president and CEO Thomas Hughes told us that fumagillin’s long double bond rich tail is troublesome, and it looks like it’s gone in both these possibilities.

Images: Zafgen and U.S. Patent Office
UPDATED: corrected image credit