The HCV Combo Race Just Got Hotter
Jan13

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. 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...

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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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From Pisces To Prodrugs: An Obesity Story
Aug25

From Pisces To Prodrugs: An Obesity Story

When it comes to obesity, the drug race between Arena’s lorcaserin, Vivus’s Qnexa and Orexigen’s Contrave is at the forefront of folks’ minds these days. But yesterday at the ACS National Meeting in Boston, I sat in on part of a session in the Division of Medicinal Chemistry that gave me a broad overview of other strategies for developing treatments for obesity. I heard a neat story from Donald L. Hertzog of GlaxoSmithKline that I thought I’d share. GSK is focusing on the melanin concentrating hormone receptor protein as a target for obesity drugs. When I read the abstract, I thought I’d made a mistake. What in the world could the pigment melanin have to do with obesity? It turns out there’s a fascinating connection. Researchers first found melanin concentrating hormone, a cyclic 19 amino acid peptide, in salmon. As you might expect, it plays a role in pigmentation of fish scales. In humans, however, the hormone doesn’t play a role in skin pigmentation. It’s made mostly in the human brain, in regions such as the hypothalamus. “When you see something released in the hypothalamus alarm bells should go off- because it could be important in feeding,” Hertzog said. That turned out to be the case. Researchers soon found that levels of the hormone go up during fasting in mice. And that mice lacking the receptor for the hormone were not only lean, they were resistant to diet induced obesity. GSK set out to make molecules that block melanin concentrating hormone receptor-1 as potential treatments for obesity. They found a promising molecule in GSK282254, which not only inhibited the receptor but as Hertzog put it, had “a lot of areas to get your hands on” for making analogs. When the GSK team replaced a simpler aromatic ring on GSK282254 with a bicyclic thienopyrimidone ring system, they saw a 15-fold boost in potency for inhibiting the receptor. After several more rounds of optimizing, they discovered GW856464, a compound that eventually made it to human clinical trials for treating obesity. Unfortunately, the molecule didn’t reach its site of action efficiently when taken orally. So GSK went back to the drawing board to find a way to improve the drug’s properties. They decided to try a prodrug approach-temporarily masking part of the drug candidate with a functional group that the body’s own enzymes will remove. Sure enough, when the team tacked the amino acid valine onto a hydroxyl group of GW856464, they made a prodrug with almost 6-fold higher bioavailability. This prodrug was selected for preclinical evaluation as a potential clinical candidate. Plenty of obesity drug strategies exist- it’ll be interesting to...

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