Liveblogging First-Time Disclosures of Drug Structures from #ACSNOLA
Apr04

Liveblogging First-Time Disclosures of Drug Structures from #ACSNOLA

Bookmark this page now, folks. On Wednesday, April 10, I will be here, liveblogging the public debut of five drug candidates’ structures. The “First Time Disclosures” Session at the ACS National Meeting in New Orleans runs from 2PM-4:55PM Central time. I am not able to conjure up a permalink to the session program, so here’s a screengrab instead. 1:20PM I’m in hall R02, where the session’s set to begin in about 40 minutes. Found a seat with a power outlet nearby, so I’m good to go! 2:29PM BMS-906024 Company: Bristol-Myers Squibb Meant to treat: cancers including breast, lung, colon, and leukemia Mode of action: pan-Notch inhibitor Medicinal chemistry tidbit: The BMS team used an oxidative enolate heterocoupling en route to the candidate– a procedure from Phil Baran’s lab at Scripps Research Institute. JACS 130, 11546 Status in the pipeline: Phase I Relevant documents: WO 2012/129353 3:02PM LGX818 Company: Novartis Institutes for Biomedical Research and Genomics Institute of the Novartis Research Foundation Meant to treat: melanoma with a specific mutation in B-RAF kinase: V600E Mode of action: selective mutant B-RAF kinase inhibitor Status in the pipeline: Phase Ib/II Relevant documents: WO 2011/023773 ; WO 2011/025927 3:47PM AZD5423 Company: AstraZeneca Meant to treat: respiratory diseases, in particular chronic obstructive pulmonary disease Mode of action: non-steroidal glucocorticoid receptor modulators Medicinal chemistry tidbit: This compound originated in part from a collaboration with Bayer Pharma. Status in the pipeline: Phase II Relevant documents: WO 2011/061527 ; WO 2010/008341 ; WO 2009/142568 4:17PM Birinapant (formerly known as TL32711) Company: TetraLogic Pharmaceuticals Meant to treat: cancer Mode of action: blocks the inhibitor of apoptosis proteins to reinstate cancer cell death Status in the pipeline: Phase II Relevant documents: US 8,283,372 5:00PM MGL-3196 (previously VIA-3196) Company: Madrigal Pharmaceuticals, acquired from VIA Pharmaceuticals, licensed from Roche Meant to treat: high cholesterol/high triglycerides Mode of action: mimics thyroid hormone, targeted to thyroid hormone receptor beta in the liver Medicinal chemistry tidbit: this molecule was discovered at Roche’s now-shuttered Nutley site. Status in the pipeline: completed Phase I trials Relevant documents: WO 2007/009913 ; WO 2009/037172 And that’s it, folks! Watch the April 22nd issue of C&EN for more on this...

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Liveblogging First-Time Disclosures From #ACSSanDiego
Mar24

Liveblogging First-Time Disclosures From #ACSSanDiego

Watch this space on Sunday as I cover the public unveiling of five drug candidates’ structures. I’ll be liveblogging the “First Disclosures of Clinical Candidates” symposium at the San Diego ACS National Meeting, which runs from 2PM to 5PM Pacific. 1:30PM It’s half an hour before the start of the session and the big ballroom is still pretty empty. Expect that to change in short order. 2:30PM LX4211 Company: Lexicon Pharmaceuticals Meant to treat: type 2 diabetes Mode of action: dual inhibitor of sodium glucose transporters 1 and 2, which play key roles in glucose absorption in the gastrointestinal tract and kidney Medicinal chemistry tidbits: this drug candidate had Lexicon’s chemists refamiliarizing themselves with carbohydrate chemistry. Most inhibitors of sodium glucose transporters incorporate D-glucose in some way. Lexicon’s chemists realized they could try something different– inhibitors based on the scaffold of L-xylose, a non-natural sugar. The team has already published a J. Med. Chem paper (2009, 52, 6201–6204) explaining that strategy. LX4211 is a methyl thioglycoside-the team went with a methyl thioglycoside because upping the size too far beyond a methyl lost activity at SGLT1. Status in the pipeline: LX4211 is currently completing Phase IIb trials. 3:00PM BMS-927711 Company: Bristol-Myers Squibb Meant to treat: migraine Mode of action: antagonist of the receptor for calcitonin gene-related peptide- increased levels of this peptide have been reported in cases of migraine Medicinal chemistry tidbits: This team recently published an orally bioavailable CGRP inhibitor, BMS-846372 (ACS Med. Chem. Lett., DOI: 10.1021/ml300021s). However, BMS-846372 had limited aqueous solubility, something that might make its development challenging. To improve that solubility, the BMS team sought to add polar groups to their molecule, something that’s been tough to do with CGRP inhibitors historically. In the end, the team managed to add a primary amine to BMS-846372’s cycloheptane ring while maintaining CGRP activity, leading to BMS-927711. Status in the pipeline: Phase II clinical trials 3:05 lots of questions from the audience for this talk! One questioner notes (as was noted in talk) that 4 CGRP inhibitors had gone before this drug in the clinic, and not made it through. Speaker notes that this candidate is more potent than others at CGRP (27 picomolar). 3:53 We’re a bit behind schedule but got plenty of good chemistry… GSK2636771 Company: GlaxoSmithKline Meant to treat: tumors with loss-of-function in the tumor suppressor protein PTEN (phosphatase and tensin homolog)- 2nd most inactivated tumor suppressor after p53- cancers where this is often the case include prostate and endometrial Mode of action: inhibitor of phosphoinositide 3-kinase-beta (PI3K-beta). Several lines of evidence suggest that proliferation in certain PTEN-deficient tumor cell lines is driven primarily by PI3K-beta....

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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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Bristol-Myers, Pfizer’s Apixaban Tops Warfarin In Anticoagulant Face-Off
Aug29

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? In 2010, we spoke with Ruth R. Wexler, executive director of cardiovascular diseases chemistry at Bristol-Myers Squibb, who explained how apixaban was designed with pharmacokinetic properties (the properties that reflect how the body affects a drug’s fate after administration) in order to reduce the risk of off-target effects. The extent to which an anticoagulant gets distributed through the body also matters, says Ruth R. Wexler, executive director of cardiovascular diseases chemistry at Bristol-Myers Squibb. “Coagulation factors are in the blood,” she says. So there’s no need for a drug candidate that blocks a coagulation factor, such as Factor Xa, to be distributed beyond the bloodstream and reach other tissues and organs. “Getting into other tissues and organs is frequently the reason why there are off-target safety issues,” she says. This was one of many concerns BMS had in mind as it developed its most advanced Factor Xa inhibitor,...

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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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