Amusing News Aliquots
May03

Amusing News Aliquots

Silly samplings from this week's science news. Compiled by Bethany Halford and Lauren Wolf Someone has actually clamped a frickin’ laser to the dorsal fin of a shark. Supervillains to take over Earth. [Wired Gadget Lab] Smalleye pygmy shark groans in disgust. It already has a light-emitting belly and doesn’t need any frickin’ laser beam. [Christian Science Monitor] Physics professor contemplates The Incredible Hulk’s energy requirements during his “getting angry” time, as well as whether he’d crack the pavement when jumping around NYC. [Wired Science Blogs] Speaking of villains, polymer chemist admits to being the evil force who made snack bags so hard to open. [Gizmodo] via [It’s the Rheo Thing] From the “Questions You Never Wondered About” files: What does one use to test a toilet’s flushing power? [Annals of Improbable Research] The obesity epidemic has escaped into the wild, with fat pigeons, fat rats, and “genuine fat asses.”...

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The Tail’s The Thing – Alkylamine Ethers and Zafgen’s ZGN-433
Jul13

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...

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Zafgen’s Obesity Drug Shows Promise, Gets Funding
Jul12

Zafgen’s Obesity Drug Shows Promise, Gets Funding

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...

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FDA’s Woodcock Talks Obesity Drug Safety
May11

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: Woodcock said the FDA would not mandate additional benefits beyond weight loss diet drugs with relatively low risks. "There are some weight loss drugs out there that don't have much serious risk and cause modest weight loss and we think that's important for people," she said. Woodcock seems to be talking about drugs already on the market, but I'm not entirely sure. (Does anyone have a transcript of this talk?) This is the kind of sentence that makes me scratch my head and ask- just where does FDA's safety bar lie? We know that the experimental pills from Arena, Orexigen, and Vivus haven't cleared it. After that trio of rejections, stimulating discussions popped up on Matthew Herper's blog at Forbes and elsewhere about whether obesity drugs are dead. But maybe the key to a weight-loss drug, as opposed to a diabetes drug that happens to have the added benefit of weight...

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Contrave Rejection and Obesity Drugs’ Future
Feb01

Contrave Rejection and Obesity Drugs’ Future

Today's a somber day for anyone looking to develop a weight-loss medication. Orexigen's potential obesity drug Contrave has failed to win FDA approval, just as Arena's Lorqess and Vivus's Qnexa before it. In other words, none of the big contenders in the diet drug race we've been covering for nearly a year has panned out. Contrave came into FDA decision-day with a a glimmer of hope behind it. Last December, an FDA panel voted in favor of approving Contrave, though they recommended that Orexigen conduct a clinical trial after approval to track the drug's cardiovascular risk. In contrast, Lorqess and Qnexa hadn't gotten a thumbs-up from the panel. But the agency turned out to be more conservative than its advisory panel. In a so-called Complete Response Letter, FDA told Orexigen it needed to conduct that cardiovascular clinical trial BEFORE Contrave could be approved, not after approval. Orexigen's stock fell over 70% on the news this morning. "Such a study would be huge, expensive, and would take years, and the request probably means that Contrave will never hit the market," writes Forbes's Matthew Herper. So where do we go from here? I hesitate to say that the obesity drug field is dead. We'll certainly continue to see scholarly papers about promising new obesity drug targets. But on the clinical side, the focus is going to have to shift away from weight loss to treating the conditions that tend to go hand-in-hand with obesity, like diabetes. That's what could help tip the safety-efficacy balance in a way that leads to new drug candidates being approved by FDA. This is not a new idea- for instance, C&EN contributing editor Aaron Rowe has covered companies' efforts to mimic bariatric surgery's beneficial effects on diabetes with a pill. Pfizer is in Rowe's story with a potential diabetes drug in clinical trials. The molecule targets an enzyme that reassembles triglycerides. One of its entries at clinicaltrials.gov says it all: "It is anticipated that PF 04620110 will have anti diabetic effects through inhibition of intestinal triglyceride absorption and potentially weight loss." Pfizer exited obesity drug research in 2008. But it didn't abandon efforts to treat some of the conditions that make obesity unhealthy. If targeting a certain enzyme happens to help with both diabetes symptoms and weight loss, so much the better. But weight loss isn't the top...

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