Two HCV Meds are Better than One for Pharmasset
Oct05

Two HCV Meds are Better than One for Pharmasset

An announcement hinting at the possibility of an all-oral hepatitis C treatment had researchers abuzz last week. Pharmasset, a Princeton, NJ company specializing in antiviral discovery, alluded to upcoming conference data that suggested a combination of ribavirin (a generic antiviral) and Pharmasset’s experimental pill PSI-7977 lowered viral counts to near-undetectable levels in a ten-patient trial (kudos to Adam Feuerstein of The Street for initial reports. . . here at The Haystack, editor Lisa Jarvis has also tracked HCV drug development for some time now). Hepatitis C virus (HCV) is a chronic liver virus with an estimated 180 million infected worldwide. Two relatively new extermination options are available: Merck’s Victrelis (boceprevir) and Vertex’s Incivek (telaprevir), approved by the FDA ten days apart last year. Unfortunately, though both drugs are administered orally, each requires co-administration of injected interferon, which can cause severe fatigue and flu-like symptoms. Both oral drugs inhibit the same enzyme: the NS3 protease, which drags down a patient’s immunity and helps the virus to produce new copies of its proteins. In contrast, the ribavirin and PSI-7977 combination involves no injections, making it easier for patients to follow the appropriate medication schedule, and lessening side effects. The PSI compound also clips a different target: NS5B polymerase, an RNA enzyme that helps viral genetic replication. In addition, the PSI-7977 is “pan-genotypic,” meaning it inhibits several genetically different strains of HCV.  A 2010 article (J. Med. Chem. 2010, 53, 7202) details the full story of PSI-7977’s synthesis. Notice anything interesting? It’s really a nucleotide strapped on to a P-chiral prodrug, a “protected” substance the body later converts to the active drug species. This P-chiral motif is seen more often in asymmetric phosphine ligands (compounds that stick to metal catalysts during reactions to modify catalyst activity) than in drug development – often chemists install drug chirality at carbon or sulfur instead. The initial drug lead was actually a mixture of both phosphorus enantiomers (“Sp” and “Rp”), until process chemists realized they could selectively crystallize out the more potent “Sp” product. In the meantime, Pharmasset scientists haven’t stopped pushing their HCV portfolio forward: a recent paper (J. Org. Chem., 2011, 76, 3782) details a new lead: PSI-352938, a cyclic phosphate prodrug attached to a purine-fluororibose nucleotide warhead. The team credits this new prodrug design with a 10-100-fold increase in potency over the “naked” adenine drug for NS5B RNA polymerase inhibition. PSI-352938 recently completed a multiple ascending dose Phase I trial, in which a daily 200 mg dose brought HCV titres down below the detection limit in 5 of 8 patients.     ...

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BARDA Bets on Boron to Bust Bacteria
Sep16

BARDA Bets on Boron to Bust Bacteria

GlaxoSmithKline recently announced a contract with the Biomedical Advanced Research and Development Authority (BARDA), a US government preparedness organization (Note: it’s not often pharma-relevant press releases come from the Public Health Emergency website!). The award guarantees GSK $38.5 million over 2 years towards development of GSK2251052, a molecule co-developed with Anacor Pharma a few years back, as a counter-bioterrorism agent. The full funding amount may later increase to $94 million, pending BARDA’s future option. The goal here is to develop “GSK ‘052”, as it’s nicknamed among med-chemists, into a new antibiotic against especially vicious and virulent Gram negative bacteria, such as the classic foes plague (Yersinia pestis) or anthrax (Bacillus anthracis). So what’s so special about this molecule? Usually, med-chemists “color” with the same atomic “crayons”: some carbon, sulfur, nitrogen, oxygen, and hydrogen, with a few halogens or transition metals every now and then (luckily, the golden age of mercury and arsenic therapies has largely passed on!). But seeing boron ensconced in a lead molecule rings alarm bells . . . you don’t usually see boron in pharmaceutical scaffolds! Look closely at GSK’052 (shown above): that’s a boron heterocycle there! Anacor, a company specializing in boron based lead compounds, first partnered with GSK in 2007 to develop novel benzoxaborole scaffolds. This isn’t the first company to try the boron approach to target proteins; Myogenics (which, after several acquisitions, became Millennium Pharma) first synthesized bortezomib, a boronic acid peptide, in 1995. Stephen Benkovic (a former Anacor scientific board member) and coworkers at Penn State first discovered Anacor’s early boron lead molecules in 2001, with a screening assay. The molecules bust bacteria by inhibiting  leucyl-tRNA synthetase, an enzyme that helps bacterial cells to correctly tag tRNA with the amino acid leucine. Compounds with cyclic boronic acids “stick” to one end of the tRNA, rendering the tRNA unable to cycle through the enzyme’s editing domain. As a result, mislabeled tRNAs pile up, eventually killing the bacterial cell. Inhibition of synthetase function turns out to be a useful mechanism to conquer all sorts of diseases.  Similar benzoxaborozoles to GSK ‘052 show activity against sleeping sickness (see Trypanosoma post by fellow Haystack contributor Aaron Rowe), malaria, and various...

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Beating Trypanosomes
Aug01

Beating Trypanosomes

Above: Triatoma sanguisuga, a bug that carries Chagas disease. Photo by Jim Gathany / Arizona Department of Health Services Late last week, a group of researchers from the University of Ibadan in Nigeria published a paper (Parasitology Res., DOI: 10.1007/s00436-011-2516-z) on several herbal extracts that can kill the parasites that cause sleeping sickness. Unfortunately, important projects like that are few and far between. I’m almost done writing an article about drugs in development to treat sleeping sickness and Chagas disease, a pair of illnesses caused by a class of protozoans called trypanosomes. My story explains that the current treatments take several weeks, and the drugs have a wide variety of side effects ranging from rashes and headaches to neurological damage and death. One of my sources seemed to be overly confident that better treatments for these diseases are just around the corner based on the early performance of several compounds that are in clinical trials.  I’m not convinced. Not long ago, a compound codenamed DB-289 entered Phase III trials for sleeping sickness. Everything seemed to be going well. And then, suddenly, the trial was halted due to safety concerns. A handful of promising new drugs are making their way through clinical trials, and a few academic labs are looking for new compounds that can kill trypanosomes. Here is a roundup of some of those substances: Phthalazines A recent improvement upon the series of phthalazines developed by Manuel Sanchez-Moreno, Fernando Gomez-Contreras, and their colleagues in Granada, Spain. Very early stage, Chagas disease DDD85646 Identified by an academic library screening project, this compound inhibits N-myristoyltransferase in the trypanosomes that cause sleeping sickness. Preclinical, sleeping sickness SCYX-7158 An oxaborole similar to the ones developed by Anacor pharmaceuticals, a company that is testing boron-based drugs for a wide variety of antimicrobial applications. Late stage preclinical, sleeping sickness. K777 An inhibitor of the protease Cruzain, developed at UCSF, it may enter human trials within a year. Late stage preclinical, Chagas disease Posaconazole Already on the market as an antifungal drug, it kills T. cruzi in vitro tests. Preclinical, Chagas Fexinidazole Developed by Hoechst and shelved, DNDi resurrected this broad-spectrum agent. Phase I, sleeping sickness. E-1224 Eisai developed this azole prodrug as an antifungal agent. It is formulated as a monolysine salt. Phase II, Chagas disease DB-289 Proved effective, but trials were halted after participants showed signs of liver toxicity and renal insufficiency. Phase III, sleeping sickness Sleeping Sickness Drug Targets Pteridine Reductase, N-myristoyltransferase, Trypanosome alternative oxidase, BILBO1, glycosylphosphatidylinositol membrane anchors Chagas Disease Drug Targets Lanosterol 14α-Demethylase, Superoxide Dismutase, cytochrome P450 sterol 14-demethylase, Cruzain Here are some great sources of further information. All about diagnostics...

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Front-line Antibiotics To Fight E. Coli
Jun17

Front-line Antibiotics To Fight E. Coli

Guest blogger SeeArrOh comments on the limited chemical weapons available to treat E.coli and its Gram-negative brethren.  SeeArrOh is a Ph.D. chemist working in industry. Yesterday’s post at In the Pipeline asking what kind of translational research should be done garnered some remarks about the importance of developing antibiotics for Gram-negative bacteria. It’s a timely appeal, because this May an especially virulent strain of the Gram-negative microbe E. coli, named O104:H4, was discovered in Germany. As reported by the Robert Koch Institute, the German equivalent of the CDC, the outbreak has (to date) killed 35 people and sickened more than 3,200. This deadly strain produces Shiga toxins, which target the kidneys, causing hemolytic-uremic syndrome, a disease characterized by red blood cell death, low platelets, anemia, and  kidney failure. These outbreaks are not uncommon, as bacteria constantly evolve and adapt. So, when a superbug strikes, why don’t we have anything better to fight it with? Vaunted antibiotics vancomycin and the methicillin derivatives won’t hinder E. coli, since they are designed to stop a different type of microbe – Gram-positive, such as Staphylococcus or Pseudomonas.  E. coli’s Gram-negative classification means that a fundamental difference in their cell walls lends them protection against certain antibiotics.  The fast reproduction rate of most bacteria, coupled with selection pressure from inhospitable environments (like new drugs), drives them to resistance even faster. Of course, we kill millions of E. coli all the time with common antibacterials: triclosan, a chlorophenol found in soaps and hand sanitizers, inhibits fatty-acid biosynthesis in both bacterial subtypes. Neosporin, familiar to many a scraped knee, contains two Gram-negative bactericides: neomycin sulfate and polymyxin B. To counter the tougher stuff, the front-line therapy against hospital-based E. coli infections has been the carbapenem antibiotics. These are extensions of the penicillin β-lactam motif, substituting sulfur for carbon, and are active against most strains of E. coli. Meropenem, first approved in 1996, was one of the first of this class, showing activity against abdominal and skin infections. Unlike penicillin, most carbapenems don’t reach the bloodstream efficiently when they are taken orally, which can limit their application. Though carbapenems may be strong antibiotics, E. coli fights back: in 2008, a bacterial enzyme was identified in E. coli taken from a patient traveling from India to Sweden, which granted resistance to the carbapenems.  This enzyme, better known as NDM-1 (New Delhi metallo-beta-lactamase-1) has the power to cleave the β-lactam bond found in most penicillin-derived compounds, thus rendering them non-lethal to the bacterium. So far, the NDM-1 variant has been found in the US, Canada, Japan, Brazil, Afghanistan, Australia, the UK, and India. Thanks to horizontal gene transfer, where...

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The Medical Metals of Yesterday
Jun14

The Medical Metals of Yesterday

SeeArrOh stumbles upon a book that’s something of a chemistry time capsule when it comes to metals and disease. SeeArrOh is a Ph.D. chemist working in industry. “That which does not kill us makes us stronger” – Nietzsche “The dose makes the poison” – Paracelsus When we look back at ancient medicine, we view the treatments once espoused as cures to be near-barbaric: bloodletting, bodily humours, exorcism, even red-hot coins on the skin. Luckily, the advent of the 20th Century brought pharmaceutical companies, sanitation, and well-managed hospital facilities, escapes from the painful and potentially fatal cures of long ago. Modern medicine would never lead us down the path to poison, would it? Maybe we didn’t leave everything from that time behind. While browsing our company bookshelves, I happened across a book entitled The Story of Chemistry with a burlap-brown cover and a thick coat of dust. Published in 1929 by a Mr. Floyd L. Darrow, it pre-dates Chemical Reviews, covering most of the 1920s in medical, agricultural, and synthetic chemistry. To calibrate you to the time period, remember that WWII had not yet occurred, so WWI is referred to as “the Great War”, and the language of science writing waxed a bit poetic, such that the author draws comparisons between “fields of endeavor” and “[the] waters of the Niagara.” I won’t try to cover all 528 pages, but I was drawn in by Chapter VII, called “Chemistry and Disease.” The author details all of the stunning advances of the late ‘20s, including the isolation of the 4(!) major Vitamins (A-D, with no extra “B-#s”, or E, or K), thyroxine, and steroids, though few chemists knew enough about the structure of these compounds to try rational drug design. (Three of the Vitamins (B1, C, D) would be synthesized in the 1930s. Poor Vitamin A had to wait until 1947.) Enter Paul Ehrlich, who won the 1908 Nobel Prize in Medicine for his “magic bullet” theory of disease treatment and the first preparation of “specifics,” or chemicals used to kill a single microorganism from among many. Salvarsan, his pioneering treatment for syphilis, was originally called arsphenamine, and contained a diarsenic core. (This was shown in 2005 to be a cyclic analogue of 5 arsenic atoms.) Back then, organoarsenics were not generally recognized as toxic to humans, and scientists would go on to synthesize several other modified versions until more tolerable therapies, such as the sulfa drugs in the 1930s, could be produced. Just two pages past Ehrlich, the author dives into more on the “specifics” of the day, including some high praise for mercurochrome. Originally derived from one of the coal tar...

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Merck Seals Hepatitis C Pact with Roche

Merck is going bare knuckles in the marketing battle for Hepatitis C patients. Just days after receiving FDA approval to market its protease inhibitor boceprevir, now known as Victrelis, it revealed Roche has signed on to co-promote the drug alongside its pegylated interferon drug Pegasys, a cornerstone of HCV treatment. Competition in the HCV arena is expected to be fierce, as Vertex Pharmaceuticals is expected to get the FDA nod to market its own protease inhibitor for HCV telaprevir, to be marketed as Incivek, no later than Monday. Both the Merck and Vertex drugs will need to be taken in combination with the current standard of care, pegylated interferon and ribavirin. Although the two drugs have never gone head to head in the clinic, telaprevir is widely considered to have a better dosing regimen and a slight safety and efficacy edge over Victrelis. As such, analysts have believed that Merck’s main advantage in the HCV market would be its ability to promote Victrelis alongside its own pegylated interferon PegIntron. Now, it will also have Roche’s sales force out there hawking Victrelis with Pegasys, as well. No financials for the deal were announced, so its hard to say at this point how much Merck is giving up in its quest for a bigger piece of the HCV market. It’s also important to note that this is a non-exclusive pact, so time will tell whether Roche and Vertex establish a similar alliance. The deal also allows Merck and Roche to “explore new combinations of investigational and marketed medicines.” As readers will recall, the ultimate goal is to eliminate the need for interferon and ribavirin, which have harsh side effects, and treat HCV using only a cocktail of pills. Roche and Merck each have promising small molecules against HCV in their pipelines: Merck has vaniprevir, an NS3/4a protease inhibitor in Phase II trials, while Roche has the polymerase inhibitor RG7128, the protease inhibitor RG7227, and the earlier-phase polymerase inhibitor RG7432. Read here for past coverage of the race to get new HCV drugs to...

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