Macrocycle Milestone for Ironwood Pharma
Aug17

Macrocycle Milestone for Ironwood Pharma

Ironwood Pharmaceuticals and Forest Laboratories last week announced submission of an NDA for linaclotide, a peptide macrocycle for treatment of irritable bowel syndrome (IBS). This is the first new drug application for Ironwood, a 13-year old Cambridge, MA company, and it could validate other companies’ strategies for large-ring drugs (covered recently by Carmen Drahl in C&EN). There’s an enormous potential market for this drug; by Ironwood’s count, a combined 45 million people in the US suffer from IBS and related chronic constipation (CC), yet few drugs are approved for these conditions. So, how does linaclotide help IBS sufferers, um . . . go? This 14-amino acid peptide ring, taken orally, arrives at the intestinal lumen, where, according to Ironwood patent literature, it docks with a receptor enzyme called guanylate cyclase C (GC-C). The extracellular domain (part that sticks out of the cell membrane), upon binding, initiates the intracellular domain (inside the cell) to begin production of guanosine-3’, 5’-cyclic monophosphate (cGMP), a signaling molecule that induces changes in the intestinal wall. In short, cGMP prompts the intestinal surface to release chloride and bicarbonate ions into the intestinal tract, which decreases sodium uptake and increases fluid secretion (Note: interestingly, this is similar to the body’s response upon E.coli infection; a bacterial toxin called ST-peptide causes traveller’s diarrhea). In Ironwood’s own words, these physiological changes “accelerate intestinal transit,” which helps to move solid waste and decrease overall pain by acting on local nerve responses. Update (3:20PM, 8/17/11) - Changed "nearly 45 million people in the US alone suffer from IBS, yet few drugs are approved for this condition" to "combined 45 million people in the US suffer from IBS and related chronic constipation (CC), yet few drugs are approved for these...

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BMS-AstraZeneca Dapagliflozin Diabetes Drug Falls Short; Pfizer’s Answer on the Horizon?
Jul29

BMS-AstraZeneca Dapagliflozin Diabetes Drug Falls Short; Pfizer’s Answer on the Horizon?

As reported by Nature News and Forbes’ The Medicine Show  on July 20, dapagliflozin, a BMS-developed diabetes drug marketed with partner AstraZeneca, was given a “thumbs-down” by an FDA review panel on July 19. After the 9-6 final vote, panel members commented favorably on the drug’s new mechanism, but evidently felt that the safety profile could not be overlooked: the FDA committee meeting statement mentions increased risk of breast and bladder cancer, increased genital infections, and perhaps most seriously, potential for drug-induced liver injury (DILI). Dapagliflozin has been one of the rising stars of the new class of Sodium-Glucose cotransporter 2 (SGLT2) inhibitors for diabetes treatment, whose development roster includes Johnson & Johnson, Astellas, Boehringer Ingelheim, Roche, GSK, and Lexicon (Note: see Nat. Rev. Drug Disc. 2010, 551 for a full recap).  The excitement behind these drugs comes from a relatively new idea for diabetes treatment: inhibition of the SGLT2 enzyme stops the kidney from reabsorbing sugar, leading to excretion of the excess glucose in the urine, which in turn lowers blood sugar. Dapagliflozin, like most SGLT2 inhibitors, is a glucose molecule with a large aromatic group attached to the carbon atom in the spot chemists call the anomeric position. Such so-called C-glycosides are thought to have improved staying power in the bloodstream relative to O-glycosides (where the linkage point is at an oxygen atom, a more common scenario in sugars), since they are less susceptible to enzymatic breakdown. So, how do you improve these compounds? A paper Pfizer published last March (J. Med. Chem. 2011, 2952) may offer some hope.  Pfizer noted that some of the C-glycoside SGLT2 inhibitors gave a positive micronucleus test, indicating their potential to damage chromosomes. To work around this liability, their chemists  designed an analog of dapagliflozin where a second hydroxymethyl (CH2-OH) group is “tied” underneath the ring, forming a bicyclic compound that advantageously rigidifies the compound, increasing potency, while at the same time blocking a potential site of reactive metabolite formation (which might contribute to further DILI). The improved compound shows high potency for SGLT2 (~920 pm), a negative micronucleus test, and is now in Phase II  trials. Want to hear more? The lead author of Pfizer's paper, Dr. Vincent Mascitti, will speak about the study as part of the Organic Division program at the ACS National Meeting in Denver - Sunday, August 28, 8:00 AM-8:30AM, Four Seasons...

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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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Remedium Technologies Gets A Grip On Severe Bleeding
May25

Remedium Technologies Gets A Grip On Severe Bleeding

In the last year we’ve covered many up-and-coming drugs for controlling the delicate balance between clotting and bleeding. But what happens when something—an injury or a major surgical procedure—overwhelms that system? Controlling big bleeds is big business, from the battlefield to the operating room. This Monday, at the American Chemical Society’s Middle Atlantic Regional Meeting (MARM) in College Park, Maryland, I heard from Matthew Dowling, CEO of a startup looking to make its mark in that space. The company is called Remedium Technologies, and it’s developing chemically modified versions of a natural biopolymer to make improved materials for stanching blood flow. Remedium is one of several companies getting on its feet with help from technology incubation programs the University of Maryland. Representatives from several of those companies, including Dowling, gave talks at a MARM symposium on the science of startups. Look here for the MARM session’s program- it includes other companies in the drug and vaccine space, including Azevan Pharmaceuticals (which C&EN wrote about in 2001 when it was called Serenix), Leukosight, and SD Nanosciences. The biochemical pathway that regulates clotting can't support severe injuries that lead to profuse bleeding, Dowling said Monday. While several treatments exist for this kind of severe injury, where sutures might not work to close a wound, they have drawbacks that Dowling thinks Remedium’s technology can address. The company’s material of choice is chitosan, a biopolymer that can be scavenged from waste shells of shrimp or crabs. Chitosan wound dressings are already on the market, but they become saturated with blood and quit sticking to tissue after about 30 minutes, which can lead to more bleeding. As a bioengineering graduate student at Maryland, Dowling developed an alternative chitosan modified with hydrophobic groups that help it stick to tissues longer. This modified biomolecule is the basis of Remedium’s technology. The company likens the material to Velcro because it is the sum total of weak interactions between hydrophobic groups and tissue that help the material stick around, Dowling explains. Once the wound has had time to heal, the material can be gently peeled away.  The chemical structure of Remedium’s hydrophobic groups is proprietary; Dowling used benzene n-octadecyl tails in graduate school. The company has two products in development- a modified chitosan “sponge” and a spray-on blood clotting foam. Neither of those products is yet available for purchase. In College Park, Dowling showed a video demonstrating how the modified chitosan makes blood congeal quickly, and how the effect can be reversed by applying alpha-cyclodextrin. In a second video, the sponge is tested on a bleeding pig that’s had a major blood vessel cut open. This presentation is similar to...

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Guest Post: The Medicinal Chemistry Reaction Cookbook- Packards and DeLoreans
May10

Guest Post: The Medicinal Chemistry Reaction Cookbook- Packards and DeLoreans

We'd like to welcome the talented SeeArrOh to The Haystack as a guest blogger. A Ph.D. chemist working in industry, you might recognize SeeArrOh from the comment threads of your favorite pharma blogs, from Twitter, or from a recent Chemjobber guest post. SAO also enjoyed the paper on what medicinal chemists actually make that caught Derek Lowe's eye yesterday. You'll notice a few similar ideas to Derek's in SAO's commentary, but a few different insights as well. Every so often, it comes up: Is there anything really new in med-chem? Is everything just a re-hash of time-honored reactions, set up with closed eyes to produce yellow oils and white solids? Or are there untapped territories ripe for exploration? Sadly, Doc Brown can’t pull up in his fusion-powered DeLorean to tell us what cancer-curing medicines await us in fifty years, so we went to the literature instead. As authors of a recent J. Med. Chem ASAP (DOI: 10.1021/jm200187y) muse: …discussions with other chemists have revealed that many of our drug discovery colleagues outside the synthetic community perceive our syntheses…[are] predominantly composed of amine deprotections to facilitate amide formation reactions, and Suzuki couplings to produce biaryl derivatives. These “typical” syntheses invariably result in large, flat, achiral derivatives, destined for screening cascades. Our intrepid British authors Roughley and Jordan - his full name, Allen Michael Jordan, was enough to entice this reader - make a case for a wide variety of possible molecular manipulation. Focusing on the output of three med-chem titans: GSK, Pfizer, and AstraZeneca, and papers from three high-impact journals (JMC, BMC, BMCL), they crunch the numbers on drug discovery synthesis and reveal some expected—and unexpected—results. Given the limited scope, the authors admit right away that their findings might not be comprehensive. But hey, let’s dive into the data anyway! As a bench chemist, I’ve run my fair share of metal-catalyzed couplings, salt formations, and acetylations, so I fully expected total domination of the list by these “workhorse” reactions. Was I right? In all, the authors analyzed 7,000 different reactions, and considered some 3,600 final compounds. Perhaps most surprising, given the recent Nobel prize given out for the mighty palladium catalysts, the C-C bond-forming reactions uncovered represented only ~10% of the total! Roughly 20% of the reactions covered are “tricks of the trade” - protecting group strategies used by chemists to deactivate or cap an otherwise reactive group of atoms. Further, half of the reactions analyzed actually couple carbon to other elements such as nitrogen, sulfur, or oxygen, so-called “C-X formation”. Only 1.5% of these reactions were oxidations, while four times as many reductions were reported. The authors speculate that...

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Finding Out Anesthetics’ Mode Of Action
Apr28

Finding Out Anesthetics’ Mode Of Action

When I think about how drug discovery has changed in the last 100 years, one of the first things that comes to mind is how much more target-focused the process is. Take aspirin as an example of the earlier model. Researchers didn't confirm how aspirin worked until John Vane's landmark 1971 paper, over 70 years since aspirin first hit the market. Compare that to today's world of drugmaking, where oftentimes researchers have to validate a target- show that it is connected to a disease and that modifying its activity might help treat that disease- before drug discovery can really get going. We've written about this process many times- see this account of the development of Lexicon drug candidate LX1031 for irritable bowel syndrome as an example. But there's at least one class of drugs where this target-based philosophy is in its infancy- anesthetic drugs. That's because researchers are only beginning to understand the molecular basis of anesthesia. So it's not clear which proteins to target or even whether you'd want a molecule that's selective for one target. The New York Times spoke with Harvard anesthesiologist Emery Brown last month about the neurobiology of anesthesia, and how being under actually is more like a coma than going to sleep. Other researchers are trying to understand anesthesia at the molecular level, like chemists Ivan Dmochowski and Bill Dailey, and anesthesiologist Rod Eckenhoff of the University of Pennsylvania. I visited their labs yesterday on a jaunt to Philadelphia. They're among a small number of research teams building fluorescent or light-reactive versions of the anesthetics used in hospitals every day*, in order to figure out what proteins they interact with and which of those are relevant to inducing anesthesia. They've got their work cut out for them- for one thing, the anesthetics that are administered by inhalation, such as isoflurane and sevoflurane, bind to a slew of proteins. But if their efforts pay off, they say they will eventually be able to help chemists build better, safer anesthetics. More reading: Molecular targets underlying general anesthesia, NP Franks, Br. J. Pharmacol. 2006, 147, S72. *by anesthesiologists like the guy I married, in the interest of full...

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