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The HCV Combo Race Just Got Hotter

BMS is shelling out $2.5 billion dollars for Inhibitex, a small pharma company with a Phase II molecule for treatment of Hepatitis C (HCV). The deal adds to the scramble for HCV assets in recent months, with Gilead agreeing to pay almost $11 billion for Pharmasset in November, and Roche’s recent purchase of Anadys. While much has been written about the merits (and price tags) of each deal, the Haystack thought it was worth taking a closer look at the chemical composition of the multi-million dollar molecules.

So what did BMS get for their money?

INX-089, Inhibitex’s lead molecule, has a common antiviral motif: a nucleoside core (the 5-membered ring sugar attached to a nitrogen heterocycle) with an amino acid based prodrug hanging off the left-hand side. Clinically-tested antivirals sharing this basic setup include IDX-184 and NM-283, both from Idenix, and PSI-352938, from Pharmasset  (For an overview of the varied structures currently in development for HCV, see Lisa’s 2010 C&EN story).

INX-089 bears a close resemblance to Pharmasset’s lead nucleotide inhibitor PSI-7977. That’s not a mistake, believes ‘089 discoverer Chris McGuigan, of the Welsh School of Pharmacy. In a recent article (J. Med. Chem. 2010, 53, 4949), McGuigan himself comments “The Pharmasset nucleoside [is] rather parallel to our early work on anti-HIV ProTides.”

Wait, what are ProTides?

Both INX-089 and PSI-7977 aren’t themselves the active viral inhibitor, but phosphoramidate “ProTide” prodrugs: compounds broken down by the body into the active drug (Chem Note: PSI-7977 has single-enantiomer Sp chirality at phosphorus, while INX-189 is a mixture of diastereomers).

Once in the body, enzymes cleave the phosphoramidate group to a phosphate (PO42-). Kinases attach two more phosphate groups, and viruses let this dressed-up molecule inside, where the nucleotide warhead inhibits HCV by interfering with RNA replication (Antimicrob. Agents Chemother. 2011, 55, 1843).

A few comments on the drug itself: The similarity of the ProTide portion (left-hand side) of the molecule to PSI-7977 really is striking: swap in an isobutyl ester and a phenyl, and it’s the same beast! The more interesting switch comes on the upper-right (“eastern”) part of the structure: a protected guanosine ring. This ring harks back to guanine, one of the four common nucleic acids found in DNA.

Source: J. Med. Chem., Pharmasset

PSI-7977, meanwhile, shows off a uracil, a nucleic acid found in RNA, not DNA.

Although it’s tempting to think such similar compounds all dock into the NS5B polymerase at the active site (in the yellow “palm” of the hand-shaped enzyme), don’t be too sure – a recent paper by Pharmasset scientists (J. Med. Chem. 2012, Just Accepted) shows quite a few “Finger,” “Palm,” and “Thumb” sites.  It’s not yet clear whether all nucleoside drugs bind to the active site in the same way. The authors also remark that, due to fast replication and mutation, potentially resistant strains of HCV pop up daily.

ARIAD Presents PACE Data; Provides Potential Gleevec Backup

Sufferers of chronic myeloid leukemia (CML), a rare and tough-to-treat blood cancer, received some good news at the 2011 Americanponatinib Society of Hematology meeting in San Diego this week. On Monday, ARIAD Pharmaceuticals disclosed new results from the Phase 2 PACE trial of its lead drug ponatinib (AP24534). The data (covered by FierceBiotech, Xconomy, and TheStreet), indicate major responses to the drug in ~40% of recipients, even in advanced or refractory (resistant to treatment) CML .

With these numbers in hand, ARIAD enters a tight race, already populated by headliners like Gleevec (imatinib), which in 2001 made a splash as a first-line CML therapy. Drugs such as Gleevec and ponatinib belong to the family of tyrosine kinase (TK) inhibitors, which dock with a mutated protein called Bcr-Abl. This protein (actually a fusion of two distinct proteins via a chromosomal mishap) triggers disease by accelerating blood cell creation, leading to uncontrolled growth and eventually CML.

imatinibSince cancers constantly evolve, new mutations in the TK active site had rendered Gleevec ineffective for certain variations of CML. Many of the PACE trial patients had previously tried newer TK inhibitors, such as Sprycel (dasatinib, BMS) and Tasigna (nilotinib, Novartis), and found that their CML had become resistant due to a single amino acid mutation in the kinase active site, which swapped a polar residue (threonine) for a carbon chain (isoleucine). So, ARIAD chemists decided to develop a drug that borrowed the best points from the earlier therapies, but capitalized on this mutation (A pertinent review in Nature Chemical Biology covers early examples of “personalized” cancer drugs developed for disease variants).

So, how did they accomplish this particular act of molecular kung-fu?  For that, we hit up the literature and go all the way back to . . . 2010. As explained in a development round-up (J. Med. Chem., 2010, 53, 4701), most approved Bcr-Abl inhibitors share several traits: densely-packed nitrogen heterocycles linked to a toluyl (methyl-phenyl) amide, then a highly polar end group, such as piperazine or imidazole. Since the mutation axed a threonine residue, the hydrogen-bond donor adjacent to the ring in earlier drugs was no longer necessary. So, chemists replaced it with a vinyl group.

A computer analysis designed to achieve better binding and drug-like properties suggested an alkyne linker might fit into the mutated active site even better than a vinyl group, so that’s ultimately what ARIAD installed. The program also suggested moving an exocyclic amino group into the aromatic (forming an uncommon imiadzo-[1,2-b]-pyridazine, green in picture). Borrowing the best stuff from other therapies, ARIAD’s chemists also wove in the “flipped” amide and -CF3 motifs (both blue) from nilotinib, as well as the methylpiperazine (red) from imatinib.Binding overlay

With computational rendering (Cancer Cell, 2009, 16, 401) ARIAD scientists could overlay both imatinib and ponatinib in the mutated enzyme’s active site (see picture, right). Notice that unlike imatinib, ponatinib avoids bumping into isoleucine 315. Ponatinib also gets a little extra binding oomph by poking its CF3 group into a hydrophobic pocket near the bottom of the active site.

Juan Enriquez Eviscerates the FDA

In this lecture, tech investor Juan Enriquez explains how the FDA’s extreme risk aversion hurts us, and why that behavior is our fault.

Biogen Idec Reveals Clinical Data for (Really) Small Oral MS Drug BG-12

Biogen Idec made a splash last week when its oral medication for multiple sclerosis (MS), BG-12, was found to reduce relapses in 44-53% of nearly 3,800 patients in two separate Phase 3 clinical trials (CONFIRM and DEFINE, respectively). Continued hopes for an orally available, non-injectable MS treatment have created a race between Biogen Idec and several other firms, as C&EN’s Lisa Jarvis examines in a 2009 MS cover story. In fact, so much has changed in 2 years that two of the six Phase 3 drugs mentioned in that article – Teva’s laquinimod and Merck’s cladribine – have already been withdrawn from competition.

So what’s the secret sauce behind BG-12? Many pharmaceuticals are small molecules with multiple heteroatoms and aromatic rings, but not BG-12: it’s just dimethyl fumarate! A search for ‘fumarate’ on pubs.acs.org returned >4800 hits, which gives you an idea of its common use in several organic reactions: [3+2] cycloadditions, Diels-Alder reactions, and Michael additions. Interestingly, dimethyl fumarate is the all-E stereoisomer; the Z-configuration, where the two esters are on the same side of the central double bond, goes by the tagline ‘dimethyl maleate’ and does not seem to possess anti-MS effects.

Very small molecules such as BG-12 (molecular weight = 144) are notoriously tough to use as drugs: they hit lots of enzymatic targets, not just the intended ones, and tend to have unpredictable side effects (see Derek Lowe’s 2005 article regarding the FDA “approvability” of several common drugs today). Toss in BG-12’s alkylating behavior to boot (fumarates can interact with nucleophilic amines or sulfides at multiple sites, including enzyme active sites), and you have to wonder how it functions in the body. Well, so do scientists. A 2011 review implicates up to 3 potential biochemical mechanisms – the Nrf2 pathway Lisa mentioned in the 2009 piece, T-helper phenotype 2 interleukin upregulation (IL-4, IL-10, IL-5, which “change gears” for immune system functioning), and CD62E inhibition, which controls adhesion of blood cells to inflammation sites.

Side notes: Flavoring chemists have added fumaric acid, the parent diacid of BG-12, to industrially-prepared foodstuffs such as baking powder and fruit juices since the 1930s. A darker side of dimethyl fumarate emerges when you consider its non-medicinal use: certain furniture companies applied it to new upholstered chairs and sofas to stop mold growth. This unfortunately caused several cases of severe skin irritation, which a 2008 exposé in London’s Daily Mail likened to actual burns.


HCV Followup: Anadys Acquired for Active Antiviral

It’s been a busy six months for new Hepatitis C (HCV) meds: first, Merck and Vertex have their drugs approved in May, and then Pharmasset leaks PSI-7977 clinical data. Now, Anadys Pharmaceuticals has just announced Phase IIb results for its clinical candidate setrobuvir (ANA-598). The pill lowered virus levels to undetectable limits in 78% of patients after 12 weeks of combination treatment with either ribavirin or pegylated interferon. Anadys notes only one major side effect, a rash occurring in 1/3 of the ‘598-treated patients. The therapy targets patients in tough-to-treat HCV genotype 1 (gen1), unlike PSI-7977, which targets gen2 and gen3.

The data seems to have convinced Roche, which acquired Anadys last Monday in all-cash deal analysts say represented a 260% premium over Anadys’s Friday stock closing price. Roche, no stranger to the HCV battle, hopes to integrate setrobuvir into a potential oral drug cocktail with its current suite of polymerase and protease inhibitors.

Setrobuvir interacts with N5SB polymerase at the allosteric “palm” binding site, located in the center of the baseball-mitt shaped enzyme. The drug’s sulfur-nitrogen heterocycle – a benzothiadiazine – is the key to virus inhibition; Anadys has installed the motif in all their HCV inhibitors, going back to their 2005 patents.

Chemists have known about the virus-targeting properties of this heterocycle for a while, but most derivatives have been culled in pre-clinical testing (see J. Antimicrob. Chemoth. 2004, 54, 14-16 for a brief review). Interestingly, chemists initially prepared benzodiathiazines, such as those in Merck’s chlorothiazide (c. 1957, according to the Merck Index), as diuretics, which found use in diabetic treatment. Over the next 40 years, modified medicines treated conditions ranging from epilepsy and cognitive therapy to hypertension and transcriptase regulation. Tweaked benzodiathiazines first showed anti-HIV and anti-CMV activity in the mid-1990s.

One final advantageous wrinkle in this structure: unlike PSI-7977, setrobuvir is not nucleoside-derived. This feature changes its binding behavior, pharmacokinetics, and even its intellectual property strategies, since many current antiviral therapies mimic the nucleosides found in RNA and DNA chains.


Takeda’s Diabetes Drug Candidate TAK-875 In Phase III Trials

Takeda Pharmaceutical today announced it has begun Phase III clinical trials of TAK-875, a first-in-class drug candidate for treating type 2 diabetes. The experimental therapy activates GPR40, a G-protein-coupled receptor that resides in pacreatic islet cells.

The TAK-875 story is as much about the biology of the target as it is about the molecule itself. And it’s a story that owes much to the company’s willingness to delve into uncharted territory.

In the early 2000s, scientists knew GPR40 existed, but didn’t know what GPR40′s purpose was in the body. Plenty of proteins fit this description– they’re called “orphan receptors” in the industry parlance. Much of Takeda’s drug discovery strategy is based on figuring out what orphan receptors do.

In a 2003 paper in Nature (DOI: 10.1038/nature01478), Takeda laid out what it learned about GPR40. The receptor responds to a variety of long-chain fatty acids. In response to fatty acid binding, GPR40 activates and boosts insulin secretion from pancreatic beta cells.

GPR40 became a viable drug target for Takeda for several reasons. First, one of the hallmarks of type 2 diabetes is a reduction in insulin secretion from pancreatic beta cells, something GPR40 activation could help counter. Second, G-protein-coupled receptors are established drug targets– and GPR40 happens to be in the class of GPCRs for which researchers know the most about structure– the Class A, or rhodopsin-like, GPCRs. (Note: other GPR-type receptors are diabetes targets as well– C&EN contributing editor Aaron Rowe has written about Arena Pharmaceuticals’ activators of GPR119 as diabetes drug candidates.)

TAK-875 docked to a model of GPR40 (ACS Med. Chem. Lett.)

Takeda used structural knowledge to its advantage in the discovery of TAK-875 (ACS Med. Chem. Lett., DOI: 10.1021/ml1000855). Researchers were able to build a model of GPR40 based on its similarity to GPCRs of known structure, and dock potential drug candidates inside to see how well they could bind.

This is far from the only drug discovery story that has to do with “de-orphanizing” orphan receptors. In fact, as far back as 1997, pharmaceutical company researchers were writing about orphan receptors as a neglected drug discovery opportunity (Trends Pharmacol. Sci., DOI: 10.1016/S0165-6147(97)90676-3). And of course, just because researchers have “de-orphanized” a receptor doesn’t mean all of the complex biology is pinned down. Case in point: the PPAR receptors (J. Med. Chem., DOI: 10.1021/jm990554g). Despite these receptors’ promise as targets for obesity and diabetes, drugs designed to target them have tanked in development or had unexpected problems after arrival on the market (read: Avandia).

So as TAK-875 enters Phase III trials, the news might be about the drug candidate’s clinical performance, but you can be sure that Takeda’s researchers are still working hard to unravel as much of GPR40′s basic biology as they can behind the scenes.

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. 




Bristol-Myers, Pfizer’s Apixaban Tops Warfarin In Anticoagulant Face-Off

Over the weekend Bristol-Myers Squibb and Pfizer announced that their blood-clot-preventing drug candidate, Eliquis (apixaban), bested the workhorse anticoagulant Coumadin (warfarin) in a large clinical trial. The results were announced at the European Society of Cardiology congress and simultaneously published in the New England Journal of Medicine. This is the first time that one of the cadre of anticoagulants seeking to replace warfarin has been shown to be superior to warfarin at preventing dangerous blood clots that can lead to strokes while also having a lower rate of bleeding compared to warfarin.

In the 18,201 patient Phase III clinical trial, called ARISTOTLE, apixaban reduced the risk of stroke in patients with an abnormal heart rhythm called atrial fibrillation by 21 percent, major bleeding by 31 percent, and mortality by 11 percent.

More statistics are available in the announcement, the journal article, and in this Forbes report, which plucks out these illustrative numbers:

The investigators calculated that for every 1000 patients treated with apixaban instead of warfarin for 1.8 years

•stroke would be avoided in 6 patients,
•major bleeding would be avoided in 15 patients, and
•death would be avoided in 8 patients.

Analysts reacted positively to the data, with Leerink Swann analyst Seamus Fernandez raising his 2017 sales estimate for apixaban by $1.1 billion to $4.1 billion in a note to investors.

We’ve previously explained how apixaban works– briefly, it blocks Factor Xa, a protease enzyme near the end of the complex biochemical pathway that regulates blood clotting. Another Factor Xa inhibitor, rivaroxaban, has been approved in Europe but awaits FDA approval. Pradaxa (dabigatran), which blocks the enzyme thrombin, has been approved by FDA for reducing the risk of stroke associated with atrial fibrillation.

So what’s the secret of apixaban’s success? Continue reading →

Beating Trypanosomes

A bug that carries Chagas disease.
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:

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

Identified by an academic library screening project, this compound inhibits N-myristoyltransferase in the trypanosomes that cause sleeping sickness.
Preclinical, sleeping sickness

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.

An inhibitor of the protease Cruzain, developed at UCSF, it may enter human trials within a year.
Late stage preclinical, Chagas disease

Already on the market as an antifungal drug, it kills T. cruzi in vitro tests.
Preclinical, Chagas

Developed by Hoechst and shelved, DNDi resurrected this broad-spectrum agent.
Phase I, sleeping sickness.

Eisai developed this azole prodrug as an antifungal agent. It is formulated as a monolysine salt.
Phase II, Chagas disease

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 for Human African Trypanosomiasis, or Sleeping Sickness, by the Foundation for Innovative New Diagnostics. Link
The rapid strip test for Chagas disease, developed by PATH. PDF Link
Here is an absolutely fantastic video of Professor Jim Mckerrow talking about Chagas disease. Link
And here’s a video of Mckerrow talking about sleeping sickness. Link
The eflornithine story. Link

Here’s my short list of what seems to be needed to beat these diseases.
A noninvasive test that can tell whether someone has stage 2 sleeping sickness, meaning that the parasites have crossed the blood-brain barrier.
Rapid tests that can tell whether Chagas disease or sleeping sickness have been cured, are getting better, or are getting worse.
Rapid tests for Chagas and sleeping sickness that use antibodies as recognition elements.
More safe, oral treatments for both diseases.

Do you have something to add? Please tell me about it. I’ll be updating this post every so often.
Aaron Rowe is this year’s C&EN Intern.

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.