Theme 7 Lectures Summarised Flashcards
Why is it crucial to file a patent once a series of interesting compounds are identified?
Patent protection allows exclusive benefits from an invention for a fixed time, typically 20 years, as a trade-off for disclosing the invention to the public
s,d,c,uniq
What are the key components of a patent?
Scope, description, and claims, with claims being crucial as they detail the invention’s unique components.
drafting and filing 6
What are the estimated costs of patenting an invention?
The costs can range from initial drafting and filing to international search reports and translations, potentially totaling around £75,000 over 6-7 years
background,invent,dd, worked examples
What constitutes the anatomy of a patent in drug development?
- Introduction (technical field and background)
- Statement of invention (restates the main patent claims i.e., what it is and does).
- Detailed description (including fall-back claims and how to carry out invention).
- Worked examples - preparations and experiments which have been carried out.
- Claims - define the invention and define what the patent should achieve. Usually 1 broad generalised claim backed up by some narrower claims.
per se,1/2,salts,
What are the different types of patent claims?
Composition of matter claim/compounds per se - If a compound has never been described before it is possible to claim the compound (per se) and compounds similar to it. This claim will cover the compound in any setting, in any form and for any use.
First medical use claim- if compound is known but not for medical use.
Second medical use claim - if compound has a medical use but not for the one in the patent.
Salt/crystalline form claim- entitles them to all physical forms of a compound if they display beneficial effects.
Composition of claims and contributions- a combination of the compound with particular excipients or other compounds.
Dosage regimen claim
Synthetic processes claim- improved methods of preparing the compound.Claims can include compounds per se, first and second medical use claims, claims for new physical forms like salts or crystalline structures, dose regimen and synthetic processes.
claims and intellectual
What can be learned from the patent case study of Atorvastatin?
Atorvastatin’s patent exemplifies the value and structure of claims in protecting the intellectual property of pharmaceuticals
Broad claims between Phar amd MERK
Why should the scope of patent claims be carefully considered?
Broad claims can be vulnerable to validity challenges, as seen in the litigation between Pharmacia and Merck over COX-II inhibitors
Why is timing considered?
It is important to file a patent early in the discovery process if there is heavy competition in the area to prevent the idea being stolen. However, patents only last 20 years from filing, so by the time the drug comes comes to market and starts generating income, there may only be 7 years or so of exclusive profit left before competitors can produce the drug under a different/generic name and profit from it.
What is more important, the examples or the claims?
Remember, it is not the examples the determine what is protected by a patent
IT IS THE CLAIMS
Searle and MERCK,(XYR1R2),Broad
How did the broadness of Searle’s patent claim for Celecoxib both benefit and hinder it?
Celecoxib by Searle and Rofecoxib by Merck were 2 selective COX-II inhibitors which were developed around the same time.
Searle sued Merck as in Searle’s patent, claim 1 was for a structure containing an X, Y, R1 and R2 of certain listed functional groups, one of which covered structure which possessed a tautomerised structure of Rofecoxib. They won this claim.
However, since the claim was so broad (due to the extensive listed options for the X, Y, R1 and R2 groups), some of the compounds claimed didn’t have selective COX II inhibitory activity, or any COX inhibitory activity at all. Therefore, Merck filed a countercase stating that since not all the compounds listed were inactive, the patent did not contain an inventive step. The judged granted for the patent to be revoked.
PPB,spm,buffer
Describe the equilibrium dialysis assay.
This in vitro assay measures the level of plasma protein binding of a drug.
A known concentration of drug is put in a semi-permeable compartment containing plasma and albumin (or other plasma protein). This compartment is placed in a buffer, and the free drug moves from down its concentration gradient from the plasma to the buffer, while bound drug remains in the compartment. The concentration in the buffer indicates the proportion of free drug.
pglyco eflux
Why is the mu-opioid agonist loperamide used as an anti-diarrhoea agent and not an opioid analgesic?
Morphine and other opioids penetrates the blood brain barrier and acts on mu-opioid receptors in the brain to reduce pain signal transmission.
Loperamide is rapidly transported out of the brain by P-glycoprotein efflux transporters in the brain, preventing it from acting there.
Instead it acts on enteric mu-opioid receptors, resulting in reduced gastric motility and increased fluid reabsorption, and therefore constipation (side effect of opioids). This can be used to treat diarrhoea with minimal side effects.
What is toxicity through mechanism-based pharmacology?
When activation of the target causes unwanted effects as well as the desired therapeutic effect.
Why are electrophiles not desired in drug or metabolite structures?
Nucleophilic attack of electrophiles by nucleophiles in the body (e.g., in proteins or DNA) result in the electrophiles becoming covalently bound which can lead to toxic effects, most commonly hepatoxicity (liver) and genotoxicity (DNA).
CY1A2, CONJ,LOSS,COV,CANCER
How does the aniline functional group cause mutagenicity?
- Aniline oxidised by CYP1A2 to aryl hydroxylamine.
- Aryl hydroxylamine undergoes conjugation via a range of transferases.
- Products of conjugation undergo acid catalysed loss of either acetic acid, water, or sulphate to generate a highly electrophilic nitrenium ion (Ar-NH+).
- Species forms covalent adducts with DNA guanines.
- Persistent mutations caused by intercalation of adducts in hotspots of DNA can lead to frameshift mutations in these hotspots, ultimately leading to cancer.
How can we avoid the presence of aniline in drugs or metabolites?
Alter the structure to remove aniline.
Prevent nitrenium ion formation via steric shielding.
Decrease nucleophilicity of aniline with an electron-withdrawing carboxylic acid or nitrogen atom to render it non-mutagenic.
Potassium,QT,Twave
What does inhibition of the human either a go-go gene (hERG) result in?
hERG is a potassium ion channel located in cell membranes in the heart which allows outflow of K+.
Inhibition of this channel causes prolongation of electrical impulses resulting in QT prolongation of electrical impulses.
A delay of the T wave by 5-19 ms can cause lack of xontrol of the heartbeat wich may lead to fatal arrhythmia.
lipohphilic
What is the hERG pharmacophore?
A lipophilic base (usualy a tertiary amine) linked to a benzene ring by a 2-5 atom chain which may include rings, heteroatoms or polar groups.
This pharmacophore allows a drug to bind to the hERG without inhibiting it and therefore preventing hERG toxicity.
p450, fexofenadine,ery/ket
What is terfenadine drug interaction can cause fatal cardiac arrythmias and why?
When given alone, terfenadine is metabolised by hepatic p450 enzymes which cause oxidation of the tert-butyl group. The resulting molecule is fexofenadine which has little hERG activity due to it being a zwitterion.
Erythromycin or ketoconazole, the hepatic p450 enzymes are inhibited meaning no oxidation can happen. Thus terfenadine has a high affinity for hERG and causes inhibition resulting in T wave delays and fatal arrhythmias.
dont understand?
What is idiosyncratic toxicity?
Toxic effects in an individual to a drug or food which we dont understand
acute, range, sub, chronic
What are the 4 stages of in vivo toxicity testing?
Acute-Studies in animals until toxicity is observed.
Range finding studies-Several doses like high,medium and low are administered daily over 2-4 weeks to establish ranges of doseswhich can be adminstered without significant toxicity and MTD.
Sub-chronic testing-animals are dosed daily for 3 months and monitored for signs of toxicity. After tissues are harvested and examined for histological changes.
Chronic testing-3+ months of animal dosing. 6-12 months for signs of toxicity, then 12-24 for obs of carcinogenicty.
highest dose
What is the NOAEL of a drug
No observed adverse effect level- the highest dose which can be administered without serious toxicity.
Determined by animal toxicity studies to help define tolerable dose for human clinical trials.
How are the effects of drugs of fertility and pregnancy assesed?
- In male and female animals measured after drug administration.
- Evaulate teratogenicity (embryonic toxicity) during early pregnancy in animals.
- Determine any effects of the drug in the final stage of pregnancy, delievry, or lactation when administred in pregnant female.
What are the 3 phases of clinical trials.
- Phase 1= 20-80 healthy volunteers monitored with increasing doses of drugs= safety and tolerance
- Phase 2-diseased patients=effectiveness and proper dosing
Data from phase 1 and 2 plans for phase 3 which is presented to FDA to gain approval and advice.
Phase 3- 100k patients of various ages, races, genders are monitored for accurate prescribing and dosing.
(either single or double blind)
Evaulates effectiveness and longterm safety.
Dossier step, filing for new drug application which is for FDA approval.
HTS, 5-chlorothiophene 2 carboxamide,compound 2, pro/pro, pharcmo
Rivaroxaban case study (development of Rivaroxaban)
- Need for DOACS identified and HTS using fluorescent substrate to identify FXA inhibitors.
- 2 hits identified. compound 1 optimised to produce compound 3 (low abosrption). SAR emphasised importance of 5-chlorothiophene 2 carboxamide for activity.
- Using this knowledge compound 2 was optimised to include this group and produced compound 4 which had 200x better potency.
- Thiomorpholine group on compound 4 subsituted for various heterocycles and 2 hits with improved potency.
- Multiple hits assessed in assay which measured prolongation of prothrombin time in rat and human blood.
- Various pharamcokinetic tests
