Overview of the drug development process Flashcards
contents
Drug discovery- key routes -Natural products -Adaptations -Side effects -Mechanism- based design -Serendipity \+All of these lead into synthesis Patient protection
Drug discovery
Synthesis (serendipity, natural products, adaptations, side effects, mechanism based)
Pharmacological screening
QSAR
(all in a triangle)–> these all lead to large scale synthesis
-12-15yrs to go from drug discovery to MA
Large scale synthesis
- Analysis (NMR, IR,MS, UV)
- Pharmacology
- Toxicology
- Biochemistry
- Formulation
Natural products 1)
- Digoxin
- Originally isolated from digitalis purpurea
Natural products 2)
- Atropine
- Originally isolated form atropa belladonna
- Greek goddess, atropa, who cut the tread of life
Natural products 3)
- Paclitaxel and docetaxel
- Paclitaxel (taxol) isolated from the pacific yew (taxis brevifolia)
- Docetaxel (taxotere) isolated form the English yew
Natural products 4)
- Isolated from a strain of aspergillum terreus
- Fungi
Adaptations (analogues) 1.
- Opiate analgesics
- Morphine
- Nalorphine
- Naloxone
- Methadone
- Pethidine
- Dextromethorphan
Analogues 2.
Pro-drugs- to overcome limertations of stability (degradation) or solubility
- Ampicillin
- Pivampicillin (is pro-drug)
- Ramapril is converted into ramaprilat= therapeutic action
Side effects
- Sildenafil (Viagra)
- Developed for treatment of angina
- Adverse effects noticed in early-phase clinical trial
Side effects
- Minoxidil (loniten)
- Vasodilator used to treat severe hypertension
- Bald men noticed increased hair growth
- Marketed for male pattern baldness (regaine)
Mechanism-based design
- HIV-1 protease
- HIV directs infected cells to make viral proteins
- Cleaved into smaller units by HIV-1 protease (prevented)
- These are used to build more virus particles
- replication and propagation of virus
Mechanism-based design
HIV protease inhibitors
- Block activity of HIV-1 protease, thereby inhibiting viral replication
- Saquinavir (invirase); Indinavir (Crixivan); Ritonavir (Norvir)
Mechanism-based design
Numerous other examples: -ACEI (e.g. enalapril) \+prevent conversion fo angiotensin | to || \+Used in the treatment of hypertension -H2 antagonists (e.g.ranitidine) \+inhibits histamine at H2 receptors (dec gastric) \+Decrease gastric acid secretion -SSRI's (sertraline) \+inhibit re-uptake of 5-HT in CNS \+Used in the treatment of depression
Serendipity Penicillin
- Discovered by chance
- Alexander flemming
- Penicillium mould killed bacterial cultures
- Large-scale testing of soil micro-organisms lead to the development of many other antibiotics:
- Streptomycin, neomycin, gentamicin, erythromycin and the tetracyclines
Serendipity Tamoxifen
- Developed as an oral contraceptive, but found to induce (rather than inhibit) ovulation
- Found to lower breast cancer incidence in lab animals
- Prevents oestrogen binding to receptors in breast tissue
Outline of product development
- New chemical entity –>
- Pre-clinical studies –>
- Clinical trials –>
- Marketed drug
Patent protection
-Typical patent lasts for 20 years
+BUT usually take out near start of discovery
+Effective patent life is much shorter
-In 2010, patents on 50% of top branded drugs expired, THEN:
+Generic companies flooded market with cheaper copies
+Major Pharma may lost 70% of scales
-Supplementary protection certificates (SPC’s)
+May be granted for up to 5 years if development has been difficult
What can big Pharma do?
-Maximise regulatory protection (e.g. SPCs)
-Adding value to product
+New formulations; new delivery systems; new indications
+Can add 10 years to patent life
-Defend patent rights
+Use courts to defend any patent infringement
+Not all patents are defensible in law
-Competing after patent expiry
+POM to OTC switch
+Market own-brand generic products
-Life-cycle management
+Balanced portfolio of products in development
+Not dependent upon sale of one product
Tricks of the trade
-Loratidine (clarityn; schering plough) withdrawn
+Replaced by desloratidine- 1 year before patent expired
+because desloratidine was a better product
-Doxazosin (Pfizer) 4mg withdrawn
+No need for a standard and modified release system
+Because the MR formulation is a cheaper and better option
-Esomeprazole (Nexium)
+S-isomer of omeprazole extended patent to 2014
