CCR5 antagonist could be used?
As a treatment for HIV
Target for HIV infection.
HIV mutates the truncation point of this receptor.
A specific point on the receptor
If this mutates the rest of the receptor is inactivated
What does the CCR5 receptor do?
Go/Gi coupled receptor
Increased intracellular calcium
Adenylate cyclase inhibition
Novel CCR5 antagonist?
Hard to find/.
Uk-107543: agonist not an antagonist.
Some are CYP450 inhibitors
Why do you not want a drug that also inhibits CYP450 and CYP2D6?
Together they metabolise 25% of all drugs
Therefore the toxicity levels of the other drugs will increase in other cellular compartments
Optimisation of UK107543?
Replacing and removing groups to change it from an agonist to an antagonist.
Then modified it to increase the potency level- side effects on the cardiac.
Increase the polarity- less absorption but no longer effects cardiac.
The optimisated compound of UK107543.
In the clinic now as HIV treatment
Properties of Maraviroc?
Highly selective CCR5 antagonist.
Antiviral activity against HIV1
Active against drug resistant strains
Mechanism of action is to inhibit interaction between gp-120 and CCR5
Major subtype of HIV
Maraviroc pharmokinetic properties?
Propertires consistent with an orally active drug
Suitable for once or twice daily dosing
Where does maravoric bind?
A deep pocket in residues TM: 1,2,3,5,6,7.
Not TM 4.
Binds to an allosteric site: block agonist.
Name the 5 things that must be studied during the pre-clinical studies?
- Efficacy studies
- Pharmacokinetic studies
- Safety/toxicity studies
- Two animal species
- Testing performed GLP
Name the 5 things that must be taken into consideration when looking at drug safety
- Regulatory guidelines
- Cellular toxicity
- Assess behaviour of animals
- Anaylse blood sample
- Histopathology assessment
Name the 5 areas of cardiovascular safety?
- Blood pressure
- Heart rate
- Cardiac arrhythmias
- Torsades de Pointe
- Blockade of the hERG channel
hERG channel blockers?
There is no key features that cause hERG.
hERG and Torsades de Pointes?
Not every drug that expresses hERG will cause Torsades de Points
However all drugs that cause TdP are hERG
A gene on chromosome 7q36.1
encodes an alpha subunit of voltage-gated, potassium channels of the eag family.
What do hERG blockers do the arrhythmia?
Increases the QT
Prolonges the heart beat.
Name the in vitro assays for hERG block and proarrhythmia potential?
lots of different assay
Best assay: electrophysiological assay.
Name the 3 In vitro and in vivo assays for drug induced arrhythmia?
- Perfused isolated heart
- Conscious piglets.
- Anaesthetised piglet
Very effective treatment for morning sickness
Deformities of eyes, heart, alimentary and urinary tract.
congenital absence of the proximal portion of a limb
Abnoramlities in the featus.
What test subjects are used for in vivo tests for reproductive toxicity?
Rabbits (mice and rats)
Non human primates
What protocol must be undertaken when doing in vivo tests for reproductive toxicity?
Daily dosing of compound during organogensis.
Assess gross abnormalities in near-term foetus.
What are the imitations to in vivo testing?
Expensive laborious and time consuming
In vitro reproductive toxicity assays?
Predictive of toxicity in humans
Cost effective and simple to perform.
Whole embryo culture test
Limitations: false positives and negatives.
Difference between in vivo and in vitro
in vivo: within the human body.
in vitro: test tube embryo.
What happens during Phase 1 of clinical trails?
Small scale: only about 50-100 people.
Cancer drugs have to be done on nonhealthy individuals as the drugs destroy cell material
What happens during phase 2 clinical trials?
Larger scale: 400-800
Relationship between dose and efficacy.
Critical information for labelling: How should they take it, side effects etc
What happens during Phase 3 clinical trails?
Large patient groups- start looking at real patients.
Estalish efficacy and safety for long term use.
Double blind placebo.
Name the major regulatory authorities
Ministry of health, labour and welfare (Japan)
Regulatory approval and registration?
Register the drug.
The regulatory authorities must approve it (roughly 18mnths)
Might outright reject it, might come back with questions or might accept it
What does the phase 5 clincical trials occur?
Monitor efficacy and cost effectiveness.
Non selective eg. paracetamol.
Trying to produce a drug that is more selective.
- AMG 517
- First in human
- Multiple dose study
- Phase 1b
TRPV1 antagonist produce?
Life threatening increases in body temp in suspetible individuals.
Cholesterol lowering drug.
Unacceptably high death rate.
Biomarker is a biochemical feature or biological process that can be used to measure the progress of a disease.
The effects of a treatment using non-invasive procedures.
Represent common biological/biochemical measures
Efficacy, pharmacokinetic, safety, predictive
Phase 0 trials?
Studies performed on small patient numbers (10-15)
Provide early PoC in huumans.
Can test the pharmaceutics properties before.
Simple translational biomarkers?
In vitro and in vivo measure of cytokine release (proinflammatory and anti-inflammatory)
Use easily accessible fluid: eg. blood
Looking at the effects of drugs in humans.
CNS drugs: distributes in the CNS.
Most drugs are concentrated in the CNS: some in the lungs and liver.
Non invasive structural imaging using magnetic resonance imaging.
Efficacy of compounds tested
fMRI (functional magnetic resonance imaging)
Use of bimarkers.
Measure the use of oxygen by neurones.
Its non selective: ie the same areas of the brain light up no matter the perception of pain by the patient