Andre cobb: Drug discovery lecture: on paper Flashcards
What is drug discovery?
Compound is found to be biologically active in the desired therapeutic area
What is drug development?
Compound that’s discovered to be biologically active that has that activity and it’s toxically optimised for the clinic
What is a me too compound?
Improvement of an existing drug that involves copying of an existing idea
Give an example of a me too compound and what compounds were formed from it?
- ACE inhibitors based on Captopril
2. Ramipril, delapril, enalapril, pedrenopril
What makes captopril good in its therapeutic area?
Chiral centre
Terminal Thyol HS-CH2
Carboxy-terminus (important for binding) CO2H
What are the five things we look for when designing a me too compound? (IMPORTANT SHIT)
- Avoidance of patent issues
- Improved efficacy- better potency and specificity of action
- Improved safety profile
- Allows for an improved formulation which is easier to administer
- Improved physical properties which affect pharmacokinetic parameters
Give an example of an avoidance of patent issues in the past when a me too compound was designed?
Amlodipine- hypertensive, a counter ion may make the patent invalid
Example:
Amlodipine maleate compared to embolden Besylate
What is cholinomimetic therapy? And describe it?
- Therapy for Alzeheimer’s Disease
- Involves targeting of Muscarinic Acetylcholine Receptors with Ach
- mAChR are located on post synaptic cell membrane of smooth muscle, cardiac muscle and glandular tissue
- Effects include: cardiac slowing, contraction of various smooth muscles (GI tract, bronchioles, seminal vesicles)
- Idea was if levels of Ach or mimic compound could be found to cause the disease, then remaining neurons could be made to compensate for those that were lost in Alzheimer’s
What does the M1 and M2 muscarinic receptors work on?
M1 localised to CNS
M2 localised to Heart and Smooth muscle
A scientist took Himbacine drug (binds to muscarinic receptors and binds it to M1 and M2 creating Kd values of 175nm and 4.6 nm respectively, which one is the drug more selective for?
- M1 divided by M2
- Value is 38
- More selective for M2
- The lower the better as you want a lower binding constant
If M1/M2 is more than one, what does this represent?
M2 is more selective
If M1/M2 is less than one, what does this represent?
M1 is more selective
Give an example of how Ribavirin (hepatitis C treatment) becomes a me too compound with improved safety profile?
- Ribavirin targets hep C virus by switching immune response to fight viruses tiling the Th1/Th2 balance
- Side effects: Haemolytic anaemia and mono/triphosphorylated metabolites affect RBC’s
- Me too compound: LEVOVIRIN- enantiomer of Ribavirin does not phosphorylate and so no haemolytic anaemia
Give an example of a improved formulation which is either easier to administer or to take?
- Drug can be a tablet instead of injection
- Modification of half life “twice a day” formulation
- Example: Loratadine lasts 6 to 8 hours in humans but adding chlorine into its structure makes it last longer and can be taken orally
What are the advantages of a me-too compound? (IMPORTANT SHIT)
- High probability of ending up with an active molecule
- Enough copies can be made which lead to a good chance of finding a compound with improvement of efficacy on original (better potency and specificity of action)
- Displays a different profile of adverse effects (improved drug safety)
- Previous information regarding appropriate pharmacological and clinical testing is available- animal models and reference data on the successful compound it’s copying from
- Work on patients who do not respond well to original drug
- Less expensive than the original
- Ocassionly very different properties can be found
- Imipramine against Chlopromazine
- Imipramine is a new anti-psychotic drug that is active against depression
What are the disadvantages of me too compounds? (IMPORTANT SHIT)
- Not very innovative
- Propping up to the pharmaceutical industry with very little effort
- Patents are often difficult to get around and original investor would have covered most variations
What are the three methods of screening compounds and explain all three of them (IMPORTANT)
Extensive screening- screening against pharmacological models (CNS, cardiovascular etc) and new chemical entities
Random screening- therapeutic objective is fixed and thousands of compounds are tested against a small number of screens without regard to structure
High throughput screening- extensive and random screening to allow thousands of compounds to be tested
What is the importance of screening?
Important in discovering lead compounds
All involve testing of compounds against a particular biological target (whole animal cells, isolated enzymes and isolated receptors)
What must a protecting group be able to do?
- Selective for the group being protected
- Must be cleaved selectively (usually over other protecting groups)
- Yields on and off must be excellent
What is combinational chemistry and the solid phase?
- Large number of molecules are produced in the same reacting pot
- Solid phase: starting reagent is attached to solid bead known as polymer support
What are the advantages of combinational chemistry for solid support phase?
- Different starting materials can be linked to separate beads so all beads can explore reagent at the same time
- Starting material and products are bound to solid support- excess reagents or unbound products can be removed by washing resin
- Intermediates in a reaction sequence are bound to the bead and do not need to be purified
What is a pharmacophore?
Particular part of structure that causes the effects
What is an analogue?
The same compound with different amount (x amount) of CH’s
What are Isosteres?
Molecules or atoms that contain the same number and arrangement of electrons
