Lazy Cakes And Melatonin: The Sleepy Snack
Jun07

Lazy Cakes And Melatonin: The Sleepy Snack

SeeArrOh has the straight dope on a controversial snack product. SeeArrOh is a Ph.D. chemist working in industry. (An homage to Terra Sigillata; it might normally be covered on his beat.) Astute readers of the New York Times may have noticed a front-page article from a few weeks back, highlighting a new late-night snack: Lazy Cakes.  Taking a cue, perhaps, from the substance-laced brownies popular in the late ‘60s, these brownies pack a decidedly sleepy secret: each contains a “proprietary calming blend” of ingredients, chief among which is melatonin.  Melatonin is a hormone usually secreted by the pineal gland (a pinecone-shaped gland located just above the cerebellum) in humans and other mammals, in response to dark surroundings.  (Note: Although they sound similar, melatonin should not be confused for melanin, the skin pigment formed by sunlight exposure) In mammals, melatonin induces the circadian rhythms associated with sleep, affects the onset of puberty and may help regulate DNA transcription.1,2 Biologically derived from tryptophan, the amino acid and purported suspect of the Thanksgiving “turkey coma”, melatonin has been shown clinically to have benefits for memory loss, in addition to antioxidant potential.  Melatonin capsules have been sold over-the-counter for insomnia and jet lag since the 1980s.  Technically speaking, the product is labeled a dietary supplement, and as such skirts regulation by the FDA.  One valid concern are possible interactions that melatonin, like other supplements, could have with prescription drugs, a topic addressed both by Terra Sig and C&E News.  More controversy over the soporific snacks springs from their colored packaging and wide availability.  This intrepid blogger ventured out into the wild to recover a sample for analysis.  The packaging, upfront, has a distinctly comic-book appeal: purple and green swirls, a trippy logo evoking That ‘70s Show, and a cartoon brownie mascot leaned back for a snooze.  The brownie itself is compact, and has quite a bit of heft for your average baked good.  The back of the wrapper evokes language usually associated with cigarette labeling: multiple tiny lines of serious text stating Recommended for Adults Only, and Do Not Drive or Operate Heavy Machinery.      The “calming blend” also includes valerian root, which is commonly found in teas and herbal supplements.  Containing sugar-decorated polycyclic lactones called iridoids, as well as valerenic acid3 derivatives, the extracts have been shown clinically to reduce anxiety and relieve insomnia.4 Passion flower extract brings a dose of alkaloids into the bedtime mix; well-known sleep inducers opium and morphine are part of this general molecular family.  The other ingredients, however, seem to just be along for the ride: current “superfruits” goji berry and açai, with the old Vitamin C standby...

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Drug Candidate Structures Revealed At #ACSAnaheim
Mar27

Drug Candidate Structures Revealed At #ACSAnaheim

1PM Pacific: There's one hour left before chemists will pack a ballroom in Anaheim to see potential new drugs' structures unveiled for the first time. Watch this space for updates. 2:39PM Pacific: CEP-26401 This drug candidate now has a name: irdabisant company: Cephalon meant to treat: deficits in cognition and/or attention in diseases such as Alzheimer's and schizophrenia mode of action: inverse agonist of histamine H3 receptor, which regulates several neurotransmitter pathways involved in cognition, attention, memory medicinal chemistry tidbits: Cephalon's goal was to bring a high quality compound to the clinic to define the utility, if any, of H3 antagonists for these indications. The team studied compounds in this area that failed. Among the things they learned was that several adverse events could be tied to drug candidates' lipophilicity. So the team prioritized lipophilicity and other such characteristics in its discovery workflow. status in the pipeline: completing Phase I in the beginning of April 2011, advancing to Phase II structure coming soon! UPDATED 3/29 with structure: 3:16PM Pacific: BMS-663068 company: Bristol-Myers Squibb meant to treat: HIV mode of action: inhibits HIV attachment to host cells by binding to the viral envelope gp120 protein and interfering with its attachment to host CD4 receptors medicinal chemistry tidbits: potency and getting the drug candidates to reach the bloodstream efficiently were key. Replacing a methoxy group on with heterocycles, such as triazoles, gave a big boost in potency. status in the pipeline: Completed Phase IIa clinical trials. Phase IIb studies are planned for later this year. 4:24PM Pacific:LX1031 company: Lexicon meant to treat: irritable bowel syndrome mode of action: blocks a subtype of tryptophan hydroxylase, the rate-limiting enzyme in serotonin synthesis, in the gut. medicinal chemistry tidbits: Lexicon started their medchem program with an open mind. They could have made a molecule that was exquisitely selective for the subtype of tryptophan hydroxylase in the gut, they could avoid hitting the other subtype by making their molecule stay out of the brain, or both. They ultimately ended up using the latter strategy, making molecules slightly on the heavy side (above 500 or 550 molecular weight) and adding groups like a carboxylic acid, that tend to keep things out of the brain. status in the pipeline: Completed Phase IIa clinical trials. 5:30PM Pacific: MK-0893 company: Merck meant to treat: type 2 diabetes mode of action: blocks the receptor for the hormone glucagon. Glucagon is released by the pancreas in response to falling glucose levels. medicinal chemistry tidbits: Merck kept several chemical scaffolds in play during this research program. But the team's big breakthrough was adding a methyl group to the benzylic position of a...

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Haystack 2010 Year-In-Review
Dec17

Haystack 2010 Year-In-Review

This Friday, we're looking back at 2010's big news in pharma and biotech, both the good and the bad. Check out our picks and be sure to weigh in on what you think we missed. 1. Provenge Approved In April, Dendreon's Provenge became the first approved cancer immunotherapy. Dendreon CEO Mitch Gold called it “the dawn of an entirely new era in medicine.” And while prostate cancer patients are excited for a new treatment option, the approval is perhaps most exciting for its potential to reignite interest in cancer immunotherapy research. There’s a lot of room for improving the approach—Provenge is, after all, expensive and highly individualized. Now that immunotherapy have been proven to work, there’s hope that the lessons learned in both its discovery and clinical development will aid scientists in inventing even better cancer vaccines. 2. Obesity Field Slims The obesity drug race played out in dramatic fashion in 2010, with three biotech companies-Vivus, Arena, and Orexigen, each making their case for its weight-loss medication before FDA. As of this writing, Orexigen's drug Contrave seems to be on the surest footing to approval, but longtime obesity-drug watchers know that caution seems to rule the day at FDA, so nothing is a sure bet. Orexigen's Contrave and Vivus's Qnexa are both combinations of already-approved drugs, whereas Arena's Lorqess is a completely new molecule. When C&EN covered the obesity race in 2009, it seemed that Lorqess (then going by the non-brand-name lorcaserin) had the cleanest safety profile, but Qnexa was best at helping patients lose weight. But FDA's panels didn't always play out the way folks expected. There were safety surprises- notably the worries about tumors that cropped up in rats on high doses of Lorqess, and the extensive questioning about birth defect risks from one of the ingredients in Vivus' Qnexa. The fact that FDA's panel voted favorably for Orexigen's Contrave, a drug that's thought to have some cardiovascular risks, generated discussion because FDA pulled Abbott's Meridia, a diet drug with cardiovascular risks, from the market in October. The dust still hasn't fully settled. Arena and Vivus received Complete Response Letters from FDA for Lorqess and Qnexa. Vivus has submitted additional documentation and a followup FDA meeting on Qnexa is happening in January. Also to come in January is the agency's formal decision on Contrave. And if you're interested in learning about the next wave of obesity drugs coming up in clinical trials, read this story in Nature News. 3. Sanofi & Genzyme: The Neverending Story Speaking of drama, Sanofi’s pursuit of Genzyme has been in the headlines for months now, and promises to stretch well into 2011. The...

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Radiochemicals, Chemists, & a Potential Alzheimer’s Breakthrough
Jun24

Radiochemicals, Chemists, & a Potential Alzheimer’s Breakthrough

The NYTimes has a great piece today on a potential new dye that can detect amyloid plaque, the telltale sign of Alzheimer’s disease. As we’ve written, the pipeline is chock full of drugs to prevent amyloid from building up on the brain, but many neurologists believe those efforts could be for naught if the drugs aren’t tested early on in the progression of the disease. The problem is that its hard to separate dementia caused by Alzheimer’s from other neurological disorders. And by the time doctors can comfortably say that a person has Alzheimer’s, an awful lot of neurons have died. To date, there’s been no way to tell if someone showing signs of memory loss will indeed go on to develop the disease. Bottom line: this new dye could help identify the right patients, earlier on, ideally improving outcomes for drugs in development and ultimately patients. The Times piece highlights the work of Daniel Skovronsky, CEO of Avid Radiopharmaceuticals, who along with University of Pennsylvania chemist Hank Kung developed a radioactive dye based on fluorine 18. Results from what could be a groundbreaking study will of the dye’s ability to detect amyloid plaque are going to be unveiled on July 11th at Alzheimer’s Association’s annual meeting. We wanted to point readers to a piece our own Beth Halford wrote back in 2008 highlighting the genesis of three imaging agents labeled with 18F, including Kung and Avid’s dye and products by Bayer and GE Healthcare. More importantly, we wanted to point out some of the potential stumbling blocks to the development of newer agents and the field in general. While the NYTimes article discusses some of the ethical hurdles associated with developing and testing imaging agents for Alzheimer’s, Halford highlighted some of the larger picture worries—namely, a lack of basic research around nuclear medicine: A report released last year by the National Academy of Sciences concluded that there was a "loss of federal commitment" to nuclear medicine. The Department of Energy, which has supported the bulk of nuclear medicine research since the 1950s, cut back its funding for the field by 85% from 2005 to 2006, and funding levels haven't made any appreciable gains in the past two years. PET researchers' other chief complaint has particular relevance to C&EN readers. "What we're missing in this field are chemists," says Gilles Tamagnan, laboratory R&D director at Molecular NeuroImaging and associate professor of psychiatry at Yale University. "There's plenty of nice chemistry to be done. There just aren't enough people doing it," he says. PET researchers say more radiochemists are required to staff the rapidly growing number of PET centers (see...

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Novartis’ MS drug Gilenia gets the green light
Jun10

Novartis’ MS drug Gilenia gets the green light

The path to approval looks clear for Novartis’ Gilenia, which is poised to be the first oral treatment for multiple sclerosis on the market. Today, members of an FDA advisory panel unanimously gave the drug a positive vote, despite worries about its side effects. Gilenia (also known as fingolimod or FTY720) is a derivative of myriocin, a compound found in a fungus that had been used for thousands of years in Chinese medicine. The drug taps into a concept similar to the one used by Biogen Idec’s Tysabri, both binding to proteins on the surface of immune cells. As we wrote last year: Once activated in the lymphatic system, T cells and other immune cells travel the busy highway known as the bloodstream to get to their target tissues. Nature has provided them with a built-in GPS: proteins that sit on the surface of the cells and point them to the proper exit ramps during their journey. In the early 1990s, scientists realized they might be able to alter the course of the disease by disabling that GPS. Biogen’s Tysabri was the first drug approved to block one of those cell surface proteins, alpha-4-beta-1 integrin, which tells the immune cells when to leave the bloodstream and enter the brain and spinal cord. Gilenia, meanwhile, binds to sphingosine-1-phosphate (S1P) receptor, a cell-surface protein that tells the immune cell to leave the lymph nodes. By doing so, some T cells are kept out of circulation, and preventing them from later reaching the nervous system. Both drugs are very effective, but there are consequences to tweaking the immune system. Tysabri was temporarily sidelined after its launch after several patients died of a serious brain infection. The company is now working on an assay to predict whether a patient is susceptible to the virus that causes the infection, but in the meantime, the safety worries have limited widespread use of what is otherwise considered the most effective treatment on the market. Gilenia, meanwhile, has its own set of side effects, including heart problems and weakened lung function. The FDA advisory panel will reportedly suggest that the company study a lower dose of Gilenia than that being proposed in Novartis’ new drug application, but the panel also said that study could be done after the drug was approved. Assuming Novartis gets the greenlight from FDA, which usually follows the advice of its advisory panels, Gilenia will be the first pill approved to treat MS (it should be noted that Acorda’s pill Ampyra addresses the neurological symptoms of the disease, rather than the underlying inflammation that causes the brain lesions in people with MS.). The...

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Obesity Musings On Alkermes, J&J News
May25

Obesity Musings On Alkermes, J&J News

I am always on the lookout for news in the obesity drug area. But lately two of the molecular components of experimental obesity drugs in late-stage clinical trials-naltrexone and topiramate- are in the news for other reasons. Alkermes announced this morning that it will receive priority review from FDA for VIVITROL, an injectable extended-release formulation of naltrexone, for treating opioid-dependent patients, with a PDUFA date of October 12, 2010. The idea is that a once-monthly injection of VIVITROL would be given to lower cravings in people with a dependence on opioids such as heroin, Vicodin, or Oxycontin. VIVITROL is already approved for treating alcohol dependence. It's Alkermes's formulation that's new. Naltrexone as a chemical entity has been around for some time. DuPont originally marketed it as Trexan in 1984 but that form is now off-patent, as C&EN's Ann Thayer wrote back in 2006. I also promised that there was an obesity connection here, and indeed there is. Naltrexone is one of the two components in Orexigen's experimental obesity medication, Contrave, as I explained last year. Orexigen has developed its own proprietary sustained-release formulation of naltrexone and the experimental drug's other active ingredient-bupropion, an antidepressant and smoking-cessation aid that boosts dopamine signaling. Ortho-McNeil Pharmaceutical, a subsidiary of Johnson & Johnson, has agreed to pay $81 million (that's $6.1 million in criminal fines and $75.37 million from civil suits) for promoting its epilepsy medication Topamax for several uses not approved by FDA. This story has been in the news for nearly a month now (see Pharmalot's entry about it here) but the company pled guilty to the illegal marketing just last Friday, placing this item back at the top of my Google News list. One of the off-label indications J&J was promoting turns out to be obesity, according to the whistleblower who brought the case. Read the legal documents here [pdf format]. Thanks to Jim Edwards at BNET for posting these. Topiramate (the active ingredient in Topamax) is one of the two active ingredients in Vivus's experimental obesity drug Qnexa. But Vivus's formulation uses topiramate at a much lower dose than would be taken as a standalone...

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