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From Blog: The Haystack

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.

From Blog: The Haystack

Zafgen’s Obesity Drug Shows Promise, Gets Funding

Beloranib. ZGN-433 is the hemioxalate salt of this molecule. (Credit- WHO Drug Information)

Zafgen, whose science has been the subject of much speculation on the Haystack (see earlier posts), has again found favor with investors, despite a tough climate for obesity drug developers. Last week, the company scored $33 million in Series C venture financing to move its drug ZGN-433 (beloranib hemioxalate) into Phase II trials (We found beloranib’s structure in WHO’s drug information Vol. 22, No. 4). This new cash comes on the heels of some fairly promising (albeit early) data the company presented at the June  American Diabetes Association Annual Meeting: in Phase Ib testing, ZGN-433 prompted weight loss without increase in disease biomarkers such as elevated C-reactive protein (an inflammation and hypertension indicator) or heightened LDL “bad” cholesterol .

Despite all that money and early signs of efficacy, plenty of uncertainty remains around the viability of ZGN-433. Zafgen admits that they still don’t know the drug’s exact mode of action in the body.  The drug’s claimed target, methionine aminopeptidase (type 2), is known to play a role in clamping off the blood supply to tumors.  In obese patients, a much lower dose – roughly 100- to 300-fold, claims the FAQ on the company website –  can signal fat tissue to release fatty acids and triglycerides back into the bloodstream; clinical data shows increased levels of breakdown byproducts in blood samples. Further, the drug is currently administered as a twice-weekly subcutaneous injection–not exactly the most user-friendly dosing method.

So what’s so interesting about this drug, from a chemistry perspective?  Well, for one thing, it has two epoxide rings that would normally raise red flags for most med chemists as potential alkylating agents. Many biomolecules have nucleophilic (electron-rich and non-hindered) reactive groups that could be trapped this way, leading to DNA mutations or protein misfolding. And that’s not all: the molecule also has an unsaturated Michael acceptor, a ketone connected directly to a double bond, which usually act as sequestering agents for glutathione in cancer models. These three reactive groups together are uncommon in any lead molecule, and the company has not stated if they observe any protein conjugation as a result.

The ultimate goal would be development of an oral variant of their lead structure, although those second-generation compounds appear to be in the discovery/preclinical phase of development. Only time will tell if these drugs will make it to market; FDA rejection of high-profile obesity drugs Qnexa and Lorcaserin still hang over conversations of new weight-loss drugs.

UPDATE: added structure 5:13PM 7/12, added “hemioxalate” to name of ZGN-433.

From Blog: The Haystack

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

From Blog: The Haystack

Zafgen Unveils Target of its Experimental Obesity Drugs: Methionine Aminopeptidase 2- UPDATED

When I first wrote about obesity drug development back in 2009 I talked with Zafgen, Inc., a biopharmaceutical company working to develop its own obesity medications. At the time, the company was keeping the molecular specifics of what they were doing pretty close to the vest. We knew from Zafgen’s website that the company was not targeting the brain like many other obesity drugs do, including lorcaserin, Qnexa, and Contrave, the three big contestants in the obesity drug race.

And we knew from articles like Luke Timmerman’s in Xconomy that Zafgen’s method is inspired by a tumor-shrinking approach developed by the late Judah Folkman and his colleague Maria Rupnick at Children’s Hospital in Boston.

Zafgen has never confirmed the molecular target for its experimental obesity drugs. Until today, that is.
At the American Diabetes Association’s annual meeting in Orlando, Zafgen unveiled that its obesity drug candidates are going after methionine aminopeptidase 2 (MetAP2), a metalloenzyme that clips methionine amino acid residues off of nascent proteins.

In addition to announcing the target, Zafgen is presenting data today from two preclinical studies of a methionine aminopeptidase 2 inhibitor, one in obese mice and another in overweight dogs.

In short, the studies suggest that inhibiting MetAP2 makes animals shed excess body weight by making adjustments to their fat metabolism and lowering their food intake. “We’re overcoming three metabolic adaptations that occur in the obesity setting that make it hard to lose weight,” says Tom Hughes, president and CEO of Zafgen.

In the long run, the company hopes to develop a pill that can mimic the effects of gastric bypass surgery, a topic C&EN covered earlier this year.

But on to the molecules. What’s the inhibitor? Well, chemists might find Zafgen’s prototype inhibitor familiar: it’s the natural product fumagillin, which Zafgen is calling ZGN-201.

“Fumagillin has been looked at for a number of indications,” Hughes says. We’ve recently covered a company working on fumagillin analogs for cancer. Fumagillin itself is on the market in France for certain kinds of parasitic infections in HIV patients who have weakened immune systems. And beekeepers use it to control a dysentery-like infection called Nocema disease in beehives. (Bees get diarrhea. Who knew?)

Though Zafgen is testing fumagillin in animals, it is not the molecule that Zafgen has carried forward into human clinical trials. The company’s ongoing Phase I trial in obese human volunteers is evaluating a different MetAP2 inhibitor Zafgen calls ZGN-433. Hughes won’t disclose the structure of ZGN-433 yet. Zafgen licensed it from another company that tried using it to shrink tumors. That didn’t work, but the other company (whose name Hughes didn’t disclose) already did safety testing on the compound. Zafgen is using that safety data to enable them to test ZGN-433′s efficacy faster than they otherwise might have.

“Fumagillin itself has limitations as a drug,” Hughes says. It’s not stable and requires refrigeration. The trouble with fumagillin isn’t so much its reactivity, Hughes says. (Fumagillin permanently attaches itself to MetAP2, an unusual-though not unheard of mechanism among drugs).

No, the problem is fumagillin’s long, double-bond-rich tail, which is prone to oxidation. “That can cause mischief,” Hughes says. Back when Folkman and Rupnick were conducting their studies, they didn’t focus on fumagillin. They instead used TNP-470, which replaces that problematic tail with another structure, Hughes says.

So does ZGN-433 look like TNP-470, or is it something else entirely? And will ZGN-433 work in obese humans the way fumagillin has worked in animals? Time will tell.

For more info: See Zafgen’s website for the posters that were presented today at the ADA meeting. (links to be added soon!)
And here are a pair of patents from Zafgen.

UPDATE 6/28: Added link to Zafgen press release, and links to mouse study poster and canine study poster.

Structures courtesy of Zafgen

From Blog: The Haystack

Celgene & Avila Forge Permanent Ties

Today brought a spate of M&A activity in the biotech space, with Amgen unveiling a $1.2 billion bid for Micromet, and Celgene agreeing to pay up to $925 million for Avila Therapeutics. Both deals brought the acquirer a drug in development to treat blood cancers, while also adding a platform technology to their research engines.

Being all about the chemistry, The Haystack is particularly interested in the Celgene/Avila deal, which involves covalent drug development technology. Celgene is paying $350 million upfront, with the promise of up to $195 million more if Avila’s lead covalent drug candidate, AVL-292, reaches the market. Pushing other covalent drugs through the pipeline could garner Avila shareholders another $380 million.

So what is a covalent drug, anyway? As C&EN’s Lila Guterman described last fall, covalent drugs form a permanent link with their target. By comparison, most conventional drugs are designed to reversibly bind to their targets—in other words, they can stick and “un-stick” to a protein.

The beauty of a covalent drug is that its specificity and potency means it can be given in low doses. As Guterman explains, patients only be given enough of the drug for molecule to reach each target protein molecule, and then another dose only when the body has generated more of that target protein. The low dose means less potential for drug-drug interactions and off-target effects.

Indeed, for years, scientists avoided developing covalent drugs out of fear that serious toxicity will arise if a covalent drug happens to permanently stick itself to the wrong protein. Check out Guterman’s piece for a cautionary toxicity tale from none other than “Rule-of-Five” inventor (and former Pfizer researcher) Christopher Lipinski.

The current generation of covalent drugs, however, is designed to assuage those fears through their highly selective and weakly reactive nature. Avila isn’t the only one banking on better molecular design leading to successful drugs: Zafgen’s obesity drug candidate ZGN433 also covalently binds to its target, an approach that—if it works—could enable it to sidestep the side effect issues that have plagued the obesity drug space.

So are these covalent drugs worth the price tag? Avila’s pipeline is relatively young, meaning there isn’t a lot of data to go on: AVL-292 is in Phase I studies in lymphomas; a compound targeting mutant EGFR is also in Phase I trials; meanwhile, two Hepatitis C drug candidates in preclinical studies. The company has also made public preclinical date on its PI3Kα-selective inhibitor (the same target as Intellikine’s INK1117, one of the drivers behind Takeda’s $190 million acquisition of Intellikine.).

From Blog: The Haystack

Haystack 2011 Year-in-Review

Well, 2011 is in the books, and we here at The Haystack felt nostalgic for all the great chemistry coverage over this past year, both here and farther afield. Let’s hit the high points:

1. HCV Takes Off – New treatments for Hepatitis C have really gained momentum. An amazing race has broken out to bring orally available, non-interferon therapies to market. In October, we saw Roche acquire Anadys for setrobuvir, and then watched Pharmasset’s success with PSI-7977 prompt Gilead’s $11 billion November buyout.  And both these deals came hot on the heels of Merck and Vertex each garnering FDA approval for Victrelis and Incivek, respectively, late last spring.

2. Employment Outlook: Mixed – The Haystack brought bad employment tidings a few times in 2011, as Lisa reported. The “patent cliff” faced by blockbuster drugs, combined with relatively sparse pharma pipelines, had companies tightening their belts more than normal. Traffic also increased for Chemjobber Daily Pump Trap updates, which cover current job openings for chemists of all stripes. The highlight, though, might be his Layoff Project.  He collects oral histories from those who’ve lost their jobs over the past few years due to the pervasive recession and (slowly) recovering US economy.. The result is a touching, direct, and sometimes painful collection of stories from scientists trying to reconstruct their careers, enduring salary cuts, moves, and emotional battles just to get back to work.

3. For Cancer, Targeted Therapies – It’s also been quite a year for targeted cancer drugs. A small subset of myeloma patients (those with a rare mutation) gained hope from vemurafenib approval. This molecule, developed initially by Plexxikon and later by Roche / Daiichi Sankyo, represents the first success of fragment-based lead discovery, where a chunk of the core structure is built up into a drug with help from computer screening.From Ariad’s promising  ponatinib P2 data for chronic myeloid leukemia, to Novartis’s Afinitor working in combination with aromasin to combat resistant breast cancer. Lisa became ‘xcited for Xalkori, a protein-driven lung cancer therapeutic from Pfizer. Researchers at Stanford Medical School used GLUT1 inhibitors to starve renal carcinomas of precious glucose, Genentech pushed ahead MEK-P31K inhibitor combinations for resistant tumors, and Incyte’s new drug Jakifi (ruxolitinib), a Janus kinase inhibitor, gave hope to those suffering from the rare blood cancer myelofibrosis.

4. Sirtuins, and “Stuff I Won’t Work With  – Over at In the Pipeline, Derek continued to chase high-profile pharma stories. We wanted to especially mention his Sirtris / GSK coverage (we had touched on this issue in Dec 2010). He kept up with the “sirtuin saga” throughout 2011, from trouble with duplicating life extension in model organisms to the Science wrap-up at years’ end. Derek also left us with a tantalizing tidbit for 2012 – the long-awaited “Things I Won’t Work With” book may finally be coming out!

5. Active Antibacterial Development – In the middle of 2011, several high-profile and deadly bacterial infections (Germany, Colorado, among others) shined a spotlight on those companies developing novel antibacterials. We explored front -line antibiotics for nasty Gram-negative E.coli, saw FDA approval for Optimer’s new drug Fidiclir (fidaxomicin) show promise against C. difficile  and watched Anacor’s boron-based therapeutics advance into clinical testing for acne, and a multi-year BARDA grant awarded to GSK and Anacor to develop antibacterials against bioterrorism microorganisms like Y. pestis.

6. Obesity, Diabetes, and IBS – Drugs for metabolic disorders have been well-represented in Haystack coverage since 2010. Both Carmen and See Arr Oh explored the vagaries of Zafgen’s ZGN-433 structure, as the Contrave failure threatened to sink obesity drug development around the industry. Diabetes drugs tackled some novel mechanisms and moved a lot of therapies forward, such as Pfizer’s SGLT2 inhibitors, and Takeda’s pancreatic GPCR agonist. Ironwood and Forest, meanwhile, scored an NDA for their macrocyclic peptide drug, linaclotide.

7. The Medicine Show: Pharma’s Creativity Conundrum – In this piece from October, after Steve Jobs’ passing, Forbes columnist Matt Herper both eulogizes Jobs and confronts a real ideological break between computer designers and drug developers. His emphasis? In biology and medical fields, “magical thinking” does not always fix situations as it might in computer development.

We hope you’ve enjoyed wading through the dense forest of drug development with Carmen, Aaron, Lisa, and See Arr Oh this past year. We here at The Haystack wish you a prosperous and healthy 2012, and we invite you to come back for more posts in the New Year!

From Blog: The Haystack

FDA’s Woodcock Talks Obesity Drug Safety

Janet Woodcock, head of FDA’s drugs center, had a few things to say about obesity drugs at Monday’s Reuters Health Summit in New York. Some of her comments weren’t surprising. But some of them might offer a sliver of hope to companies hoping to succeed where Arena Pharmaceuticals, Orexigen Therapeutics, and Vivus have so far failed– in bringing a new diet pill to market.

From a Reuters story, which was brought to my attention via Twitter by David Pittman, a former C&EN contributor now working at FDA News (Thanks for the tip, David!):

For diet drugs, Woodcock said companies might find success by showing benefits beyond weight loss such as a decrease in blood pressure or reversal of diabetes.

“Those would be benefits you might accept more risk for,” Woodcock said. The FDA recently rejected diet drugs with various safety issues from Arena Pharmaceuticals Inc (ARNA.O), Orexigen Therapeutics Inc (OREX.O) and Vivus Inc (VVUS.O). The agency also asked Abbott Laboratories Inc (ABT.N) to withdraw its diet medicine, Meridia, from the market due to heart risks and the company agreed.

It’s not surprising to hear Woodcock say that a potential weight loss pill’s risks must be balanced by clear benefits. Having positive effects on things that can be consequences of obesity, such as blood pressure and blood sugar control, is one way of achieving that balance. Another way is to show FDA that your risks aren’t all that risky. On that topic, I was intrigued to read Arena’s announcementthat it isn’t conducting the 12-month study FDA asked for to evaluate how its obesity drug candidate lorcaserin caused tumors in rats, and is conducting a three-month study instead.

Now, what really caught my eye in Woodcock’s statements was this gem: Continue reading →

From Blog: The Haystack

A Proton-Transporting Protein As An Obesity Drug Target

No matter how disappointing obesity drug research seems to be these days, I can’t resist a good story about a hot biological target in the obesity area. And if obesity isn’t a hot enough topic for you, add in the fact that the company chasing this target, Energesis Pharmaceuticals, happens to be co-founded by a veteran of Sirtris Pharmaceuticals, and the spotlights shining on this story start to look mighty bright.

But I won’t be talking about red wine compounds today. Instead, the focus is on brown fat. Today in Xconomy, Ryan McBride gives a great overview of Energesis, which is aiming to treat obesity, diabetes, and metabolic syndrome by harnessing brown fat’s power.

McBride’s article has a good amount of detail on the company itself but I was intrigued by what seems to be an important molecular target for the company’s strategy: uncoupling protein-1.

So what is this protein? Continue reading →