Liveblogging First-Time Disclosures of Drug Structures from #ACSDallas
Mar19

Liveblogging First-Time Disclosures of Drug Structures from #ACSDallas

Watch this space, chem-keteers. Starting at 2PM Central time TODAY, I'll be continuing my spring tradition of live-blogging the public unveiling of drug structures from ACS Dallas. This spring's symposium, unfortunately, only contains one true 'reveal' - schizophrenia drug candidate AQW051, from Novartis. The other structures are already public. (Three were covered at prior ACS meetings and are part of a 'where are they now' talk). I've included vintage hand-drawn structures to refresh our collective memories.   UPDATE 12:00PM Central time- screengrab of the afternoon's program 1:40PM - grabbed a seat in the second row, by a power outlet. Wifi seems to be behaving. May the liveblogging commence! If you're on Twitter, watch #ACSMEDI and #ACSDallas hashtags. 2:45PM AQW051 Company: Novartis Institutes for BioMedical Research Meant to treat: cognitive impairment associated with schizophrenia (ie, impairment to memory and decision-making) Mode of action: partial agonist at the alpha7 nicotinic acetylcholine receptor Medicinal chemistry tidbit: Novartis started with a lead called JN403, but cardiotoxicity issues limited progress with this molecule. high throughput screening led to 11 chemical families, including quinuclidine ethers, which led to AQW051. Hurth's team noticed that changes to the molecule's phenyl moiety made big differences in selectivity for related receptors and other parameters. Status in the pipeline: Phase II clinical trials Related documents: WO2007068476, WO2007068475, WO2006005608, WO2005123732, WO2004022556; Bioorg. Med. Chem. Lett. 2009, 1287-1291 3:30PM MK-1064 (see above for structure) Company: Merck Research Laboratories Meant to treat: insomnia Mode of action: selective orexin 2 receptor antagonist Medicinal chemistry tidbit: MK-1064 is a more selective version of Merck's dual-orexin receptor antagonist suvorexant, which after setbacks is on the cusp of reaching the market. Research suggests that orexin 2 plays the primary role in wakefulness, so a more selective antagonist could provide relief from insomnia. Merck’s early orexin 2 receptor antagonists were not sufficiently selective and had metabolic issues (eg, pump proteins). Lowering molecular weight and blocking metabolic hot-spots led to MK-1064 Status in the pipeline: Completed Phase I clinical trials Related documents: ChemMedChem 2014, DOI: 10.1002/cmdc.201300447 ; BMCL 2013, 23, 6620 3:56PM asunaprevir and BMS-791325 (now has generic name - beclabuvir) (structures above) Company: Bristol-Myers Squibb Meant to treat: hepatitis C virus Mode of action: asunaprevir inhibits viral NS3 protease; beclabuvir inhibits viral RNA polymerase, however, it is not a nucleoside mimic and so binds outside the polymerase active site Status in the pipeline: Phase III clinical trials Among several clinical tests discussed in Dallas, asunaprevir and beclabuvir were tested as part of a triple-drug cocktail with daclatasvir, BMS's experimental NS5A inhibitor. Phase 2b study-The triple regimen dosed for 12 weeks achieved cure rates of up to 94%. Related...

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How Jagabandhu Das made dasatinib possible
Jan16

How Jagabandhu Das made dasatinib possible

In my story on how drugs get their generic names for this week's issue of C&EN, I briefly discussed how the chronic myelogenous leukemia medication Sprycel (dasatinib), mentioned in this Haystack post by SeeArrOh, ended up being named after Bristol-Myers Squibb research fellow Jagabandhu Das. Even though Das, or Jag, as his coworkers call him, didn't discover the molecule that bears his name, the program leader for Das's team, Joel Barrish, says dasatinib wouldn't have existed without him. So how'd Das make a difference? About one and a half years into the search for a kinase inhibitor that might be able to treat chronic myelogenous leukemia, "we were hitting a wall," Barrish, today vice-president of medicinal chemistry at BMS, recalls. "We couldn't get past a certain level of potency." Early on, the team's work suggested that a 4'-methyl thiazole was critical for potency. Replace the methyl with a hydrogen, and potency went out the window. But Das challenged that dogma, Barrish says. He thought the compound series had evolved to the point where it would be a good idea to go back and test those early assumptions. His hunch paid off-- in the new, later kinase inhibitor series, it turned out that removing the methyl group from the thiazole actually boosted potency. Thanks in large part to that discovery, the team eventually was able to make kinase inhibitors with ten thousand fold higher activity. "Jag didn't stop there," Barrish says. After debunking the methyl dogma, Das found a way to replace an undesirable urea moiety in the team's inhibitors with a pyrimidine group, which improved the inhibitors' physical properties. With help from Das's two insights combined, eventually BMS's team came up with the molecule that became dasatinib (J. Med. Chem., DOI: 10.1021/jm060727j). Generic naming requirements are extensive, but the committees involved in the naming process are willing to use inventors' names as long as they fit the criteria. But sometimes, Barrish says, "there's luck involved in who makes the final compound." In the dasatinib story, though, it was clear that Das's discoveries were the keys to success. When dasatinib was in clinical trials and it came time to put forward a set of possible generic names for consideration, Barrish didn't have to think too hard about who was most responsible for his team's success. "It was very clear in my mind that it was Jag," he says. So he added dasatinib to the list. "I admit, it was one of those things you do and you kind of forget about it, thinking, 'oh, they'll pick something else'," Barrish says. When dasatinib ended up being the name of choice, he...

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In transition again, but in the best possible way
Jun17

In transition again, but in the best possible way

Well, it actually happened, and I can’t believe my good fortune. I have a job! And not just any job, but one in medicinal chemistry, in a similar role to the one I had before my, um, involuntary hiatus. I’ve recently begun work at my new position. I’m now a Senior Research Chemist at The Lieber Institute for Brain Development in Baltimore, adjacent to Johns Hopkins Hospital and School of Medicine. I’m very excited, and couldn’t be happier. Yes, I know, there’s nothing about this job that’s “nontraditional” at all for a chemist. It is a big change going from industry—Big Pharma, no less—to what is primarily an academic setting. It is, of course, an even more drastic change moving from the ranks of the unemployed to the un-unemployed. The only downside, if there is any, about my new job is the commute. Comparatively, though, it is a very minor inconvenience—I mean, I get to go home every night and be with my family. Many of my former colleagues, although employed, are not so fortunate in that regard. To say that I’m extremely lucky is a huge understatement, particularly in this economy. As many of you know all too well, chemistry jobs are few and far between these days. I fully expected to move to a career outside the lab, if not outside chemistry altogether. I had worked on professional development activities, such as project management training, to prepare myself for such a move. Being able to blog about what I’ve been going through has been very therapeutic, no question. It’s forced me to work through my feelings about becoming unemployed in a supportive (and very public) environment. I’m very grateful for the opportunity to contribute this blog, and hope to continue doing so as long as the opportunity remains. While I’m ecstatic about this turn of events, I also feel something bordering on survivor guilt. It’s not that I feel undeserving—I am good at what I do. But many, many other people are, too. The fact that so many good chemists have had to leave the discipline hurts science as a whole. To my former colleagues and other fellow chemists still trying to find a job—although I know all too well how difficult things are, try not to despair. There are positions out there—there’s just an insane amount of competition for each one. I realize this is probably cold comfort to many of you who have been out of work far longer than I had been. What can I offer in the way of advice? Looking back, I cannot understate the value of networking to help secure a...

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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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