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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Nonracemic Synthesis of GK−GKRP Disruptor AMG-3969
Hi Folks, it was a busier week than normal and I finally got a chance to work on a post. There is no witty title here, either. I couldn’t think of one. I wanted to find something with some structures to draw because I haven’t posted anything of that nature in a while. I originally thought I found a process development paper in JOC, but I was in error. I decided to post about it anyways, because it hits on some points that process chemists will identify with.
The post can be found in J. Org. Chem. 2014, 79, 3684−3687, doi: 10.1021/jo500336e. Lead author is Matthew P. Bourbeau and colleagues at Amgen. The paper is about the rework of an API synthesis. The original synthesis was used to produce material but when your final product is racemic and being separated using SFC or SMB chromatography at the final step, it…
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Flu and other viral infections could be stopped by boosting natural protein
Boosting a naturally occurring protein may help the body to detect and fend off certain viral infections on its own.
The discovery could lead to new, more effective treatments for many dangerous viruses – such as hepatitis C and influenza.
In a new study published in the journal Immunity, researchers from the University of Pittsburgh Cancer Institute (UPCI) detailed their investigation into the protein oligoadenylate synthetases-like, or OASL. They revealed that by amplifying OASL in human cells, they were able to effectively inhibit viral replication.
According to the researchers, OASL is a key component of the body’s innate immune system, a subsystem of the overall immune system that allow our cells to intrinsically defend against pathogens.
“It was initially thought the [adaptive] immune system is all we have to protect against invasion – the one that makes antibodies and cells that can essentially destroy infected…
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Antibodies from the desert as guides to diseased cells
With help of proteins, nanoparticles can be produced, which bind specifically to cancer cells, thus making it possible to detect tumours. Credit: CBNI, UCD
Nanoparticles are considered a promising approach in detecting and fighting tumour cells. The method has, however, often failed because the human immune system recognizes and rejects them before they can fulfil their function. Researchers at Helmholtz-Zentrum Dresden-Rossendorf and at University College Dublin have developed nanoparticles that bypass the body’s defence system and find the diseased cells. This procedure uses fragments from an antibody that only occurs in camels and llamas.
The use of nanoparticles in cancer research is considered as a promising approach in detecting and fighting tumour cells. The method has, however, often failed because the human immune system recognizes the particles as foreign objects and rejects them before they can fulfil their function. Researchers at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) and at University College…
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Cleaning Validation
Cleaning Validation
Cleaning validation is primarily applicable to the cleaning of process manufacturing equipment in the pharmaceutical industry. The focus of cleaning validation is those cleaned surfaces that, if inadequately cleaned, could potentially contaminate the product subsequently manufactured in that same equipment.
This primarily covers product contact surfaces in the cleaned equipment. Cleaning validation is not performed only to satisfy regulatory authorities. The safety of patients is the primary objective, and product contamination presents serious liability issues for any pharmaceutical manufacturer or contract organization.
The history behind cleaning validation
The unhygienic conditions in Chicago’s meat- packing plants revealed in Upton Sinclair’s novel, “The Jungle”, allowed the government investigators and congress to enact the meat inspection law and the Pure Food and Drugs Act in 1906, the law forbade adulteration, misbranding adulteration, misbranding of foods, drinks, and drugs.
Thirty years later the drug tragedy “elixir of sulfanilamide” which killed over…
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cGMPs for Active Pharmaceutical Ingredient (API) and Excipient Production
Polyphenols and Alzheimers
“Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the growing population of elderly people. A hallmark of AD is the accumulation of plaques in the brain of AD patients. The plaques predominantly consist of aggregates of amyloid-beta (Abeta), a peptide of 39-42 amino acids generated in vivo by specific, proteolytic cleavage of the amyloid precursor protein.” (Finder & Glockshuber)
Stefani & Rigacci review the evidence for polyphenols and their ability to reduce amyloid aggregation. Natural polyphenols are emerging as an increasingly attractive treatment for amyloid disease prevention and therapy. Evidence suggests that they can inhibit the production of amyloidogenic peptides, increase antioxidant enzyme activity and reduce inflammation. The researchers suggest that we should now be describing them as potentially multitargeting drugs.
Potential sources of polyphenols are found in, amongst others, vegetables, fruit and green tea.
Grape consumption may offer benefits for symptomatic knee osteoarthritis
New research presented last week at the Experimental Biology conference in San Diego, California, suggests that regular grape consumption may help alleviate pain associated with symptomatic osteoarthritis of the knee, and improve joint flexibility and overall mobility. Researchers attribute these potential benefits to the polyphenols found in grapes.
The sixteen week clinical study, undertaken by Texas Woman’s University, was designed to investigate the benefits of grape consumption on inflammation and osteoarthritis outcomes. 72 men and women with knee osteoarthritis (OA) were assigned to either consume grapes in the form of a whole grape freeze-dried powder, or a placebo powder.
The study results, presented by lead investigator Shanil Juma, Ph.D., showed that both men and women consuming a grape-enriched diet had a significant decrease in self-reported pain related to activity and an overall decrease in total knee symptoms. This beneficial effect was more pronounced in females. Additionally, age-related differences were observed:…
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Grape-enriched diet supports eye health
New research presented this week at the Association for Research in Vision and Ophthalmology conference in Orlando, Florida suggests that regular grape consumption may play a role in eye health by protecting the retina from deterioration. Specifically, a grape-enriched diet resulted in a protective effect on retinal structure and function.
The retina is the part of the eye that contains the cells that respond to light, known as photoreceptors. There are two types of photoreceptors: rods and cones. Retinal degenerative diseases affect over 5 million people in the U.S., and can cause blindness due to photoreceptor cell death.
The study was conducted by a research team at the University of Miami, Bascom Palmer Eye Institute and investigated whether a diet supplemented with grapes could protect the photoreceptors in mice with retinal degeneration. Mice were either fed a grape-supplemented diet corresponding to 3 servings of grapes per day for humans…
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TIC 10 structure established……Synthesis: Structural misassignment stems from long-standing use of incorrect recipe to prepare anticancer agent
Misassigned (top) and corrected (bottom) structures of bioactive TIC10.
PIC FROM
Don’t forget the chemistry
In a bit of a whoopsie it has come to light 1 that a compound TIC10, a stimulator of gene expression for TRAIL and in PhI/II clinical trials has in fact got an incorrect structure or rather the compound that was protected in the patent was assigned the incorrect structure. It was patented in a single compound patent 2 – which might ring alarm bells for some – were they really that confident they had the best compound. A quick look at the patent revealed large amounts of in vitro work but none in vivo again begging the question how good is this single compound. The compound had been identified by a group at Pennsylvania State University and licensed to Oncoceutics from screening of the NCI compound collection but the team, as reported, only attempted structural characterisation by MS. This would be unlikely to differentiate regioisomers which is what the problem turns out to be. It does however seem strange that the patenting error was not detected during resynthesis and scale-up for progression to the clinic. The error was picked up when a group from the Scripp’s 3 who synthesised the patented compound but found it inactive while they found the NCI batch to be active. They characterised the patented (inactive) and non-patented (active ex NCI) structures by crystallography and total synthesis. The corrected structure has now been patented by the Scripps group and licensed to Sorrento.
Of course this is all a bit embarrassing for those concerned but also more seriously could end up with extensive patent litigation, wasting money and discouraging investors from supporting the work until the patent situation is clarified causing delay in progressing the asset. Please please talk to medicinal chemsist early in a project this one looks like no one did which has led to an expensive mistake.
1. S. Borman Chem Eng News 2014, May 26 page 7
2. US Patent US8673923
3. N. T. Jacob et al Angew. Chemie. Int. Ed., Article first published online: 18 May 2014 DOI: 10.1002/anie.201402133
The fog is beginning to lift on how a mistake in the structural analysis of a promising drug candidate occurred and was sustained for so long that the agent was nearly in human clinical trials before the error was discovered.
Kim D. Janda and coworkers at Scripps Research Institute California recently discovered that the structure of a promising cancer drug candidate, called TIC10 or ONC201, had been misassigned in the agent’s patent (Angew. Chem. Int. Ed. 2014, DOI: 10.1002/anie.201402133). The biotech firm Oncoceutics, which has licensed the patent (U.S. 8673923), is sponsoring Phase I/II human clinical trials for the agent, which are currently in a prerecruitment phase. But Scripps has applied for a patent on the corrected structure and has licensed it exclusively to another company, Sorrento Therapeutics (C&EN, May 26, page 7).
TIC10 originated with a 1973 German patent (2150062) owned by C. H. Boehringer Sohn, in Ingelheim, now called Boehringer Ingelheim. The now-expired patent covers a family of 43 compounds, one of which is now called TIC10, and their possible use as antiseizure medications. It also contains a recipe for synthesizing the compounds.
At some point, the National Cancer Institute (NCI) picked up TIC10 for its publicly accessible Diversity Set II database, which researchers can screen freely to find agents with interesting activities. The compound’s structure shown in the database listing was the same as in the German patent—with three rings fused in a linear fashion.
Wafik S. El-Deiry of Pennsylvania State University and coworkers discovered that NCI’s TIC10 sample had potent anticancer activity (Sci. Transl. Med. 2013, DOI: 10.1126/scitranslmed.3004828). They used mass spectrometry to try to confirm that the structure of the compound was the same as that listed in the NCI database. But MS is inadequate for structure confirmation when used on its own.
Penn State was granted a patent to use TIC10 to treat cancer, and it licensed the patent to Oncoceutics for development. The company used the Boehringer recipe to develop a production process to produce sufficient amounts of the compound for study and eventually for clinical trials.
When Janda’s group decided to study TIC10 for possible use in a combination therapy, they opted to synthesize the three-ring linear structure from scratch, instead of using the Boehringer recipe. The compound they made that had that structure was bioinactive, so they ordered the compound from NCI and found that agent to be bioactive. When they then analyzed the bioactive agent carefully, they found it to have a structure in which one of the three fused rings is at an angle to the other two. They then synthesized this angular structure from scratch, applied for a patent on it, and relicensed it.
The reason the structural problem with TIC10 persisted so long is that until Janda’s group joined the TIC10 game, others all seemed to be using the Boehringer recipe to make it and were thus synthesizing a bioactive but structurally misidentified compound.
Oncoceutics Chief Business Officer Lee Schalop notes that all of the company’s research on ONC201, including studies required for approval of the agent’s Investigational New Drug Application with the Food & Drug Administration, were carried out with the bioactive agent. Oncoceutics did not reply by C&EN press time to an inquiry about what techniques it used to characterize ONC201 during its studies.
A number of reagent suppliers have also been marketing TIC10 for research purposes. A search of Chemical Abstracts Service databases in May showed that eight companies were selling CAS Registry Number 41276-02-2, the compound with the misassigned linear structure. (CAS is a unit of the American Chemical Society, which publishes C&EN.)
Sigma-Aldrich, one of the companies offering TIC10, hired a contractor to synthesize TIC10. But the company didn’t officially launch the compound for sale and didn’t ship any to customers. In response to the Janda publication, Sigma-Aldrich halted the product launch.
Sorrento patent attorney Jeff Oster tells C&EN that a meeting between Oncoceutics and Sorrento had been scheduled to begin untangling some of TIC10’s patent and licensing issues. But Schalop says Oncoceutics has no plans to meet with Sorrento.
Researchers discover new form of cancer
This is the story of two perfectly harmless genes. By themselves, PAX3 and MAML3 don’t cause any problems. However, when they combine during an abnormal but recurring chromosomal mismatch, they can be dangerous. The result is a chimera—a gene that is half of each—and that causes biphenotypic sinonasal sarcoma. The tumor usually begins in the nose and may infiltrate the rest of the face, requiring disfiguring surgery to save the individual. Because Mayo Clinic pathology researchers have now described the molecular makeup of the rare tumor, several existing cancer drugs may be targeted against it. The findings appear in the current issue of Nature Genetics.
In 2004, Mayo Clinic pathologists Andre Oliveira, M.D., Ph.D., and Jean Lewis, M.D., first noticed something unusual about a tumor sample they were analyzing under the microscope. By 2009, they had seen the same pathology several times and had begun collecting data. In 2012…
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