Natural Product Sources Flashcards
What extracts are best seen as sources of chemically diverse libraries of compounds?
Natural product extracts
What percentage of currently used medicines are from microbial or plant sources?
Approximately 60%
What are the sources used to screen natural products?
Fermentation/microbial sources
Plant/herbal sources (parts of plant e.g. Bark, root, leaves, fungi)
Marine sources (like sponges)
What is the process of progressing form a natural product to a hit?
The whole natural product extract is screened for activity.
If it is found to be active. The active constituents undergo bioassay directed purification which involves fractionating an extract (using chromatography) into a range of fractions that contain different natural products in each fraction.
Subsequent bioassays of each fraction will reveal which ones contain the active compounds. This is repeated until compounds are obtained in the pure form.
Structure of active compound is then determined, usually by spectroscopic techniques like NMR.
Once pure, active compound is classified as a hit and progressed to further testing
What are examples of compounds that have been discovered and extracted from natural sources?
Statins: Zocor, Xenical,
Anticancer agents: Daunomycin and taxol
Asntibtiocs: vancomycin
What is particular about drug discovery from natural plant sources?
Often the active compounds have amazingly complex structures that no one would ever have envisaged or attempted to synthesise
What is analogue synthesis?
A structure activity relationship is usually developed in this process. This is a model which allows us to predict what features of the active compound are helpful for bioactivity and which features are not.
Why are analogues synthesised?
To optimise the structure and activity of the compound.
All analogues are then evaluated for bioavailability, ultimately leading to a most active analogue
What are huge main critical factors which must be determined for an experimental drug?
Its absorption, distribution, metabolism and elimination
What are one of the most common factors which causes most lead compounds to fail in clinical trials?
Its lack of efficacy, side effects or toxicity
How are the problems of leS compound failure due to lack of efficacy, side effects or toxicity overcome?
Many companies are now undertaking ADME studies earlier in the drug development process
Also utilising computational methods more to try and predict mde properties (known as chemoinformatics)
What is absorption and bioavailability?
How well the drug is absorbed into bloodstream when given orally or intravaneously.
Is it unchanged by metabolism
What physical parameter can be determined and used to predict absorption and bioavailability?
Log P. This can be correlated to how well a drug may be absorbed
What is distribution and elimination?
Drugs are distributed about various fluid compartments of the body and are eventually eliminated as the drug or it’s metabolised products.
Tissue distribution studies in animals can determine if the drug reaches the target organ and whether or not it accumulates at various sites
What sort of markers are used in tissue distribution studies?
Radiolabelled 3H or 14C.
This labelled drug is also used to determine the routes and time course of elimination
What is metabolism?
This typically leads to inactivation of a drug where body uses enzymes to derivatise the molecule to make it more amenable to excretion.
The main processes include oxidation, reduction or hydrolysis followed by coupling to carbohydrates,
What is metabolite identification important for?
FDA registration
Where does metabolism predominantly take place in the body?
The liver, so liver homogenates can be used to assess the metabolic fate of isotopically labelled drugs
Why is a patent needed?
Patient in provides the basis for exclusivity of the manufacture, use and sale of pharmaceuticals, and thus allows the return on the development costs of drug development
What are the three main types of patents?
Composition of matter
Use
Process
What is a composition of matter patent?
The most valuable type. This includes a description and claim to some chemical entity or structurally related series.
Patent discloses physical properties, method of preparation and some designated utility.
The basic requirements of this patent is that the subject must be novel and un obvious i.e. Not easily produced from someone else’s material
What is a use patent?
These can be filed on known compounds with the claim being that there is a previously unreported and un obvious pharmacological activity.
Companies can claim new uses for their own drugs or they can claim a new use for competitor’s drugs
What is a process patent?
These describe a novel or improved method of synthesising a previously described compound
I.e. A different or better way of a asking something e.g. Omeprazole
How long does a patent last?
20 years from the date of issue.
What happens after the patent has expired?
The patented drug comes out of patent protection and it typically leads to the production of the rug as generics- produced by some other company e.g. Zovirax (aciclovir), Zantac (ranitidine), Prozac (fluoxetine)
The loss of market can be very dramatic
What kind of a financial threat do generic drugs pose on branded drugs?
Once the patent has expired, generic drugs quickly overtake the sales of branded drugs.
Sales data suggest it takes only 6 months before generic drugs pick up 80% of the share of sales.
What are the ways of defending a brand drug name?
Re formulate
Rebrand
New indications
What is reformulation?
Allows a company to develop better products, build a franchise, limit the impact of generics e.g. Prozac Weekly was approved by the FDA Two years after the original patent ended, for the same continual treatment phase of major depressive disorder.
PW contains 90mg of fluoxetine with an enteric coating which delays the release into the bloodstream. This formulation takes advantage of the protective effects provided by fluoxetines naturally long half life, requiring PW only to be administered once a week.
The new formulation was patented as an improved method of delivery which is safer and improved patient compliance. This stops other companies selling selling PW until 2017
What is rebranding?
Where pharmaceutical companies give a new brand name to a molecule and introduces it into a new market.
E.g. July 2000: the FDA approved Eli Lilly’s sarafem for the treatment of premenstural dysphoric disorder. It contains the same active ingredient found in Prozac.
The additional patent protection also helps with educational efforts for the largely under recognised disorder. Is also reduces confusion about the differences between depression and PMDD
Sarafem became the first prescription medicine indicted for the treatment of PMDD in the US
What are new indications?
Where companies sell the product too treat a wider range of diseases, so the overall volume is not as heavily affected.
E.g. New indications for antidepressants like Prozac include treating for OCD, panic disorders and other anxiety/stress conditions.
These new indications are often heavily pushed by sales reps of the pharmaceutical companies, ensuring doctors remember their products and reminding doctors of all the conditions that their drugs can be used to treat.
When is the best time to file a patent?
Companies will want to patent its new drug as late in the development as possible to allow more time for it to live when the drug is on the market so that the company can gain its return of the development costs.
However, they risk another company patenting the drug.
What does a provisional patent mean?
The applicants have one year to file a full patent.
These are useful as the date of the filing (priority date) will help define who patented first, but the year of the provisional patent does not count against the term of the issued patent.
What happens during the lead optimisation phase?
The companies chemical process development group undertakes the synthesis of bulk quantities of the raw drug substance .
The drug is then formulated providing suitable dosage forms for clinical purposes
Toxicity studies are also initiated in several animal species, investigating the metabolic disposition and pharmacokinetic properties of the drug.
What happens if findings in the lead optimisation phase are untoward?
Further development of the drug may stop.
What happens if the drug survives all the studies in the lead optimisation phase?
Company will file an investigational new drug application with the US FDA. This is a formal request to begin the clinical trials of the drug
Why are clinical trials undertaken?
To finally evaluate the ability of the compound to provide benefit to humans
How many phases of clinical trials are there?
Four phases:
1) clinical pharmacology and toxicity
2) initial clinical investigation for treatment effect
3) full scale evaluation of treatment
4) post marketing surveillance
What is clinical pharmacology and toxicity?
This is the first phase of clinical trials.
The studies conducted in this phase are concerned with the safety of the compound.
Studies are performed on ~20-100 health volunteers
What are the three small studies undertaken in the clinical pharmacology and toxicity phase (phase1) of the clinical trials
1) single dose (often low dose) on health males
2) rising dose studies to determine an acceptable single dose via route of interest, on health males/females. This helps to establish the therapeutic range
3) food interaction studies in both health male/females
What other studies are undertaken simultaneously in the clinical pharmacology and toxicity phase (phase 1) of the clinical trials?
Drug metabolism and bioavailability studies
When would drugs be given to unhealthy volunteers in the clinical pharmacology and toxicity phase (phase 1) of the clinical trials?
When drugs that will most likely have toxic effects e.g. New anticancer drugs.
Any serious adverse effect will usually result in trials being aborted
What is the probability of the drug making it into the market once it has surpassed the clinical pharmacology and toxicity phase (phase 1) of the clinical trials?
15%.
The cost of trials to this point is ~$5.4M NZD
What does the initial clinical investigation for treatment effect phase (phase 2) of the clinical trials test for?
Safety of the new compound and beings to monitor efficacy in the selected patient population.
Typically divided into 2 stages
What are the 2 stages of the initial clinical investigation for treatment effect phase (phase2) of the clinical trials?
1) proof of concept trial- where a limited trial is conducted in selected patients to ascertain the drug has some degree of efficacy
2) more broad range trial - which involves a larger number of patients often trial lying two different dose strengths. Required to refine the optimal dosage and determine the best way to administer the drug
How are trials in the initial clinical investigation for treatment effect phase (phase2) conducted ?
Typically on a double blind bias.
Many Regulatory agencies also require a positive control group where patients are given a known drug
Why is a positive control group required in the initial clinical investigation for treatment effect phase (phase2) of the clinical trial?
to validate both the trial and to demonstrate the new drug has comparable or superior efficacy and an equivalent or superior safety profile
When is a placebo not given in the initial clinical investigation for treatment effect phase (phase2) of the clinical trial?
In the case of life threatening diseases such as cancer,
The new drug is compared to a known medication
How long do phase II trials take?
2 years, often involving 200-500 patients
How likely is the drug to succeed in the market if it has surpassed phase II clinical trials?
nearly 50%.
Phase II requires $80M NZD
What is the full scale evaluation of treatment phase (phase3) of the clinical trials?
This consists of two global trials at 2 dose strengths with ~2000 people per trial
The dosages used are important as these are the doses to be used if the drug is marketed,
Testing is always conducted as double blind vs. Placebo/currently use drug
Different racial groups will often be included to investigate a possible difference between ethnicities
How long to phase III clinical trials last?
Usually 2 years, but can take as long as 8 years if a patient numbers are low.
The trial will run as long as needed to obtain sufficient info for the application to be made to the US FDA for a new drug application
The FDA then takes 18 months to decide
What percentage of the drug gets into the market once it has surpassed phase III clinical trials?
More than 90%. This has costed $1.1Billion NZD
What is phase IV of the clinical trials?
Post marketing surveillance
Occurs after drug approval
Involves monitoring of adverse effects and additional long term, large scale studies of drug efficacy. These studies can also help identify additional new uses for the drug
What is a clinical example of post marketing surveillance?
Merck has recently reduced its top selling arthritis and acute pain medication, Vioxx.
A study conducted in huge use if Vioxx in treating colorectal polyps discovered patients had an increased probability of CVD events beginning after 18 months of treatment compared to those taking placebo.
Merck has another drug, Arcoxia which treats arthritis and pain they are hoping to transfer patients onto without any overall loss of income.
Vioxx has already easily made back the money spent on its research and development, so they can afford to let it go, still having made an overall profit
If we knew the molecular structure of the desired target, what would drug discovery then require?
Experimental structure determination, 3D protein structures as templates for model building, Comparative modelling, Sequence of novel therapeutic targets Virtual libraries 3D models of therapeutic targets High throughput docking (in silico screening of compounds on 3D targets) Structure based library design Hits, Structure based analogue design Less
What is virtually screening?
The process of using computational methods to design molecules which fit into the binding pockets on the protein
This involves high level docking calculations that require powerful computers.
What happens after virtual screening?
Chemists then synthesise the molecules and perform bioassays,
The programmes will usually design molecules than bind extremely efficiently
What is a limitation of virtual screening?
The computer doesn’t always design molecules that are easy to make.
It also takes a lot of time to generate these structures for assay. They may be too complicated
What is an example of structure based design?
Relenza (anti influenza medication)
Inhibits salidase on the virus which mediates the hydrolysis of a polysaccharide. This is an important step in the release of new virus particles from an infected cell.
To design new inhibitors of the enzyme, they crystallised the enzyme with a compound related to the normal sialic acid substrate.
Resultant X-ray crystallography 3d structure allowed visualisation of the active site of enzyme.
By modelling this active site, they could design molecules that would fit into it very tightly due to close interactions of opposite charged functional groups and close alignment of hydrophobic groups.
After modelling, target compounds were prepared and screened against the enzyme, leading to the discovery of Relenza.
What is the result of tighter interactions with the active site of the enzyme in the case of Relenza ?
Lowers the substrate turn over capacity of the enzyme,
The result of enzyme inhibition is the inability of the virus to replicate and move about the body
What is a limitation of Relenza?
They found their drug had no oral bioavailability and was only active when taken directly into lungs using an inhaler device.
This limited their sales and opened up the market to its competitors. Tamiflu (sold by Roche) was then developed using “me-too” philosophy as an oral alternative to Relenza.
How was Tamiflu a better drug than Relenza?
Tamiflu took the design of Relenza and adapted it to fit lipski’s rulers with the sole aim of making a good oral drug.
Tamiflu currently outsells Relenza on a 100:1 ratio
Why did the pharmaceutical company AstraZeneca encourage all doctors to convert patients taking their anti ulcer treatment Losec to the newer drug Nexium?
Losec = omeprazole, sold as a racemic mixture. Only one isomer is active. The other isomer is inactive and completely safe
Nexium = esomperazole. Name is derived from s isomer of the racemic drug.
40mg of Losec has the same effect as 20mg of Nexium and to date, no clinical trial has shown any valid reason for taking Nexium over Losec.
AstraZeneca’s composition of matter patent had elapsed on Losec so by converting patients to Nexium, the company still has the financial advantage over their competition.
