What Are Your Favorite Non-U.S. Drug Discovery Stories?
Jun18

What Are Your Favorite Non-U.S. Drug Discovery Stories?

Over at my other gig at the Pharma & Healthcare section of Forbes.com, I’ve been covering a few stories of new drugs and improvements on old drugs. Although I’m focusing on natural products like vancomycin and semi-synthetics like lurbinectedin, I’ve been thinking a bit about the stories behind the discoveries of all drugs. Part of my thinking has been driven by my current reading of Happy Accidents: Serendipity in Modern Medical Breakthroughs by Morton A. Meyers, MD, professor emeritus of radiology and internal medicine at SUNY–Stony Brook. Therein, I’m reading stories like that of Gerhard Domagk, who first showed that prontosil was an effective antibiotic in vivo but not in vitro because it liberates sulfanilamide when metabolized. The story was told in even greater detail in the superb Thomas Hager book, The Demon Under the Microscope. This got me to thinking: I hear quite a bit about drug discovery stories in the U.S. but rarely about modern drugs that have been discovered elsewhere. The brain tumor drug, temozolomide, for example, was developed in the laboratory of Malcolm Stevens at Aston University building upon work of the late Tom Connors (expertly told by Kat Arney at Cancer Research UK last summer). But one rarely hears stories like these, even in pharmacology courses at pharmacy schools where the teaching is more likely to be chemistry-oriented. So, chemistry world hivemind: What are your favorite stories of drug discovery and development that didn’t occur in the United States? Bonus points for natural products or...

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Mourning Open Notebook Science Pioneer, Dr. Jean-Claude Bradley
May14

Mourning Open Notebook Science Pioneer, Dr. Jean-Claude Bradley

I’ve have more later but I just learned some very sad news from Antony Williams: Drexel University chemist, Jean-Claude Bradley, passed away yesterday. Antony has some personal reflections of his dear friend at his site but here is the official letter from Drexel: Dear Members of the Drexel University Community, It is with deep sadness that I inform you of the passing of Jean-Claude Bradley, PhD, associate professor in the Department of Chemistry. Jean-Claude joined Drexel as an assistant professor in 1996 after receiving his PhD in organic chemistry and serving as a postdoctoral researcher at Duke University and College de France in Paris. In 2004, he was appointed E-Learning Coordinator for Drexel’s College of Arts and Sciences, helping to spearhead the adoption of novel teaching modalities. In that role, he led the University’s initiative to buy an “island” in the virtual world of Second Life, where students and faculty could explore new methods of teaching and learning. Jean-Claude was most well known for his “Open Notebook Science”(ONS), a term he coined to describe his novel approach to making all primary research (including both successful and failed experiments) open to the public in real time. ONS, he believed—and demonstrated—could significantly impact the future of science by reducing financial and computational restraints and by granting public access to the raw data that shapes scientific conclusions. “…In the past, trusting people might have been a necessary evil [of research],” Bradley said. “Today, it is a choice. Optimally, trust should have no place in science.” In June of 2013, Jean-Claude was invited to the White House for an “Open Science Poster Session,” at which he discussed ONS’ role in allowing he and his collaborators to confidently determine the melting points of over 27,000 substances, including many that were never before agreed upon. Currently, his research lab had been working to create anti-malarial compounds to aid in the synthesis of drugs to fight malaria. His lab’s work on this project was made available to the public on a wiki called UsefulChem, which Jean-Claude started in 2005. Jean-Claude’s philosophy of free, accessible science translated to an open approach in the classroom as well. Content from his undergraduate chemistry courses was made freely available to the public, and real data from the laboratory was used in assignments to practice concepts learned in the classroom. In an article in Chemistry World last April, Bradley said: “It is only a matter of time before the internet is saturated with free knowledge for all…People will remember those who were first.” Indeed, we will remember Jean-Claude as a pioneer in the open access movement, an innovative researcher and colleague,...

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New University of Florida Chemistry Building Is A “Go!” – Again
May06

New University of Florida Chemistry Building Is A “Go!” – Again

Well, it’s that time of the academic year to dust off my University of Florida doctoral regalia for this weekend’s commencement activities at my North Carolina institutions. It’s always a delight to be reminded of my graduate school days in UF’s Department of Pharmacology and Therapeutics. So, I was pleased to receive an email from UF that, last Thursday, the Florida Legislature really, really appropriated $20 million to complete the long-planned new Chemistry Building. According to Jeff Schweers of The Gainesville Sun: Construction money includes $20 million for a new chemistry building, UF officials said. With the $15 million it received last year and $7 million before that, UF has $42 million toward its needed $60 million to replace the outdated, cramped, chemistry building built in 1947 with one that can meet the growing demand for class and lab space. The University of Florida has had a chemistry program since the university’s inception in 1906. Master’s degrees were first awarded in 1909 and Ph.D.s in 1930. While the current chemistry facilities are not quite that old, their renovation and replacement are a bit overdue. In 2008, C&EN ranked Florida among the top 25 U.S. schools producing chemistry graduates at all three levels (C&EN article, 23 November 2009, pg 38, by David J. Hanson). I’m impressed that the state of Florida has taken advantage of their $1.2 billion budget surplus to reinvest in the state’s higher education system. Both Florida and Florida State are receiving additional funds for recruitment of world-class faculty and will provide faculty raises after five years of no increases. Republican Governor Rick Scott has indicated that he will sign the $77.1 billion budget. Since I left Gainesville, I’ve continually come across Gator Chemists in my professional travels. Here in North Carolina, I’ve worked with no fewer than three Florida Chemistry Ph.D.s. Much of my contact with chemists during my graduate years was with those in the medicinal chemistry department in the College of Pharmacy, “down the hill” at the J. Hillis Miller Health Center complex, before construction of the new Pharmacy building. But I attended a few seminars at the old chemistry building, usually on my way up to the Purple Porpoise (R.I.P) for oysters, wings, and cheap pitchers of beer. So, congratulations to all of my colleagues at UF. It’s great – to be – a Florida (Chemistry)...

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Google Features Percy Julian, Legendary African-American Chemist
Apr11

Google Features Percy Julian, Legendary African-American Chemist

What a fantastic surprise this morning on the 115th anniversary of Percy Julian’s birth:     I’m beside myself with joy to see this pioneering chemist be recognized by the most prominent search engine in the world. I don’t know where to begin about Julian but I’m sure that many of you have seen The Forgotten Genius, the PBS-produced NOVA life story of the chemist. Julian suffered many indignities in his training, from being denied dormitory residence while earning his B.S. at DePauw University to progression to racial issues limiting him to a M.S. at Harvard. He later completed his Ph.D. work at the University of Vienna in 1931. Julian is probably best known for using natural products as a template for making drugs. His first major feat, the synthesis of physostigmine, a cholinesterase inhibitor from the Calabar bean used to treat glaucoma has been recognized by ACS as a National Historic Chemical Landmark at DePauw University. This 11-step synthesis from phenacetin, the active metabolite of acetaminophen, was completed with his Vienna colleague, Josef Pikl, and students in the laboratory. Julian synthesized cortisone, estrogen, progesterone, and testosterone from the Calabar bean compound, stigmasterol. Later, at Glidden Paint Company, a happy accident led Julian to find that soybean extract (soya oil) also contained the 17-member sterol nucleus, a much more accessible source. At this time, we had absolutely no treatments for rheumatoid arthritis. But cortisone, then made by Merck in a laborious 36-step synthesis, was found in 1949 to transform the treatment of rheumatoid arthritis. However, Merck’s starting material was deoxycholic acid from bovine bile. Julian’s synthetic work beginning with sigmasterol. I could go on. So I strongly suggest that readers consult the ACS National Historic Chemical Landmark dedication and, please, watch The Forgotten Genius. You should buy the DVD, as I did for teaching in my pharmacology classes, but you can watch it in segments at the PBS NOVA...

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The Case Of The Malodorous Metabolite
Apr06

The Case Of The Malodorous Metabolite

Over where I also write at Forbes.com, Matthew Herper, Senior Editor for Pharma and Healthcare, reported on GlaxoSmithKline’s NEJM clinical trial of darapladib in coronary artery disease. The drug had been developed as a small molecule, orally-formulated, subnanomolar inhibitor of lipoprotein-associated phospholipase A2. Lp-PLA2 is associated with apolipoprotein B-containing lipoproteins, such as LDL and non-HDL particles, and is found in the necrotic center of atherosclerotic plaques. Formerly known as platlet-activating factor acetylhydrolase, the enzyme produces pro-apoptotic lysophosphatidylcholine and stimulates the synthesis and release of proinflammatory mediators such as IL-1 beta, IL-6, ICAM-1, and VCAM-1. A meta-analysis of nearly 80,000 patients across 32 trials indicated that Lp-PLA2 was associated with a relative risk for coronary artery disease of 1.10 for each 1-standard deviation increase in activity, even when correcting for other influences. This magnitude of relative risk is similar to that for non-HDL cholesterol or systolic blood pressure.So, the enzyme seemed like a reasonable target for small-molecule inhibition. Darapladib (SB-480848) emerged from screening for inhibitors and a synthesis campaign, each published in 2002 and 2003, and was selected for clinical trials. A study with 330 patients with coronary artery disease, The Integrated Biomarkers and Imaging Study-2 trial, showed that 12 months of darapladib (160 mg daily, p.o.) decreased the progression of atherosclerotic plaques that occurred in the placebo group, even when they were also receiving standard-of-care statin therapy. Last week saw the publication in NEJM of the STABILITY trial to examine efficacy against primary endpoints. Unfortunately, this large, placebo-controlled, randomized trial with 15,828 patients who took 160 mg darapladib once daily showed no benefit of the drug relative to placebo in the primary endpoints of time to cardiovascular death, myocardial infarction, and stroke. However, the drug did show significant differences from placebo in measures of major coronary events (9.3% vs. 10.3 % for placebo) and total coronary events (14.6% vs. 16.1% for placebo). Major coronary events were defined as “a composite of death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia.” Total coronary events were defined as “a composite of death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization procedure.” But when looking at other aspects of the paper, Herper noted that a small but significant subset of patients reported an unpleasant odor from their skin, urine, or feces while taking darapladib. In discussing the side effects relative to the modest effects on secondary endpoints, Herper wrote, [T]he leading side effects were diarrhea (3.2% vs. 0.8%), feces odor (2.2% vs. 0.1%), urine odor (1.4% vs. <0.1%), and skin odor (2.2% vs. 0.1%). Would such a small difference be enough to...

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