ND - Drug Development Flashcards
What are 2 examples of small-molecule drugs?
Natural compounds:
- Normally produced by organisms
- penicillins: bacterial cell wall
- rapamycin: mTORC1 inhibitor
- morphine: found in a number of plants
(Semi) Synthetic Chemistry:
- modified natural compounds (semisynthetic)
- libraries of chemically synthesised compounds
What are the 4 main ways a drug can be developed?
Natural isolate: This is where a drug is isolated from a natural source, such as a plant or animal.
Semi-synthetic: This is where a natural product is chemically modified to create a new drug with different properties.
- For example, heroin is a semi-synthetic opioid that is derived from morphine.
Synthetic: This is where a drug is created entirely in the laboratory, without using any natural product as a starting point.
- Most modern drugs are synthetic.
Look-alike that acts as an inhibitor: This is a type of synthetic drug that is designed to mimic the structure of a natural compound, but to have a different effect.
- For example, naloxone is an opioid antagonist that can be used to reverse the effects of an opioid overdose.
Do small molecule modulators need to look like their endogenous counterparts?
No
What are some examples of endogenous opioid agonists? (3)
- Enkephalins: penta peptide
- B-Endorphins
- Dynorphins
Why do we need new drugs? (6)
- Emerging diseases or previously untreatable ones
- Improved action (lower toxicity)
- Altered pharmacokinetics (A.D.M.E.)
- Cheaper synthesis
- Competition
- Resistance
What stages are involved in a typical pharmaceutical drug pipeline? (7)
1) Early stage R & D
2) Preclinical studies in animal models
3) Phase I: Safety
4) Phase II: Efficacy, safety
5) Phase III: Efficacy, Safety
6) FDA Review and approval
7) Post approval
What is involved in Phase I studies? (3)
To define the pharmacology, route and metabolic fate in humans
- Initial dose is usually 1/20 or 1/50 of the effective dose in animals
- Side-effects monitored by clinical biochemistry etc
- Small numbers studied - typically 36 or less
What is involved in Phase II studies? (3)
To define therapeutic profile and dose regimen
- Dose-ranging means that a lot of data are at sub-optimal doses
- Patients usually studied and larger numbers cf. Phase 1
- Limited number of clinical centres involved
What is involved in Phase III studies? (3)
To determine clinical efficacy compared to placebo / comparator
- Greater duration of treatment and larger numbers studied
- Multi-centre and often multiple indications investigated
- Close monitoring of compliance, other drugs and side effects
What is involved in Phase 4 studies- post marketing surveillance? (3)
Clinical practice is less controlled than Phase 3 studies
- Larger numbers and more diverse patients treated
- Adverse drug reactions (ADRs) are reported by practitioners
- Black triangle drugs - all ADRs and events should be reported
What are different types of targets for small molecular weight molecules?
- Active sites of enzymes: kinases, metabolic enzymes, neuronal enzymes (acetyl-choline esterases)
- Receptors : GPCR, RTK
- Ion channels:
- Protein/ Protein interaction sites
What is important for a robust detection system in drug screening?
Adequate frequency of positive and negative control values with a reasonably small standard deviation for each.
What is Alzheimer’s disease (AD) and how can it be treated?
Alzheimer’s disease (AD) is a neurodegenerative disease
Two approaches exist:
- Symptomatic treatments aim to improve symptoms like memory loss. (e.g., drugs increasing acetylcholine)
- Etiologically based treatments aim to slow/halt progression by targeting the underlying cause.
Explain the connection between AChE inhibition and potential treatment for Alzheimer’s disease.
In Alzheimer’s disease, the breakdown of acetylcholine (ACh) by AChE is increased.
- ACh is a crucial neurotransmitter for memory and learning.
By inhibiting AChE with drugs, this assay system helps identify candidates that could potentially increase ACh levels in the brain, thereby aiming to improve symptoms associated with Alzheimer’s disease.
What steps are involved in the ADP Depletion Assay? (4)
- Sample: Add a cell or mitochondrial sample to the reaction mixture.
- Kinase Reaction: Add an ATP-generating system (kinase reaction) to the mixture. This system will convert ADP to ATP.
- ADP-Glo™ Reagent: Add ADP-Glo™ reagent to the mixture. This reagent will stop the kinase reaction and convert remaining ADP to a luminescent signal.
- Luminescence Measurement: Measure the luminescence using a luminometer. The luminescence signal is proportional to the amount of remaining ADP
