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Flashcards in Drug discovery 2 Deck (48):
1

CCR5 antagonist could be used?

As a treatment for HIV

2

CCR5 receptors?

Target for HIV infection.

7TM domains.

HIV mutates the truncation point of this receptor.

3

Truncation?

A specific point on the receptor

If this mutates the rest of the receptor is inactivated

4

What does the CCR5 receptor do?

Go/Gi coupled receptor

Increased intracellular calcium 

Adenylate cyclase inhibition

5

Novel CCR5 antagonist?

Hard to find/.

Uk-107543: agonist not an antagonist.

Some are CYP450 inhibitors

6

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

7

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.

 

8

Maraviroc?

The optimisated compound of UK107543.

In the clinic now as HIV treatment

9

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

10

HIV1?

Major subtype of HIV

11

Maraviroc pharmokinetic properties?

Propertires consistent with an orally active drug

Suitable for once or twice daily dosing

12

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.

Inhibits activation

13

Name the 5 things that must be studied during the pre-clinical studies?

  1. Efficacy studies
  2. Pharmacokinetic studies
  3. Safety/toxicity studies
  4. Two animal species
  5. Testing performed GLP

14

Name the 5 things that must be taken into consideration when looking at drug safety

  1. Regulatory guidelines
  2. Cellular toxicity
  3. Assess behaviour of animals
  4. Anaylse blood sample
  5. Histopathology assessment

15

Name the 5 areas of cardiovascular safety?

  1. Blood pressure
  2. Heart rate
  3. Cardiac arrhythmias
  4. Torsades de Pointe
  5. Blockade of the hERG channel

16

hERG channel blockers?

There is no key features that cause hERG.

 

17

hERG and Torsades de Pointes?

Not every drug that expresses hERG will cause Torsades de Points

However all drugs that cause TdP are hERG

18

hERG?

A gene on chromosome 7q36.1

 encodes an alpha subunit of voltage-gated, potassium channels of the eag family.

19

What do hERG blockers do the arrhythmia?

Increases the QT 

Prolonges the heart beat.

AS17

20

Name the in vitro assays for hERG block and proarrhythmia potential?

lots of different assay

Best assay: electrophysiological assay.

21

Name the 3 In vitro and in vivo assays for drug induced arrhythmia?

  1. Perfused isolated heart
  2. Conscious piglets.
  3. Anaesthetised piglet

22

Thalidomide?

Hypnotic 

Sedative

Anxiolytic drug

Very effective treatment for morning sickness

Caused teratogenicity 

23

Teratogenicity?

Phocomelia

Deformities of eyes, heart, alimentary and urinary tract.

 

24

Phocomelia?

congenital absence of the proximal portion of a limb

25

Teratogenicity?

Abnoramlities in the featus.

26

What test subjects are used for in vivo tests for reproductive toxicity?

Rabbits (mice and rats)

Non human primates

Zebra fish

27

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.

28

What are the imitations to in vivo testing?

Expensive laborious and time consuming

Species difference

Developmental differences

29

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.

30

Difference between in vivo and in vitro

in vivo: within the human body.

in vitro: test tube embryo.

31

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

32

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

33

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.

 

34

Name the major regulatory authorities

FDA (USA)

EMEA (Europe)

Ministry of health, labour and welfare (Japan)

35

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

36

What does the phase 5 clincical trials occur?

Monitor efficacy and cost effectiveness.

 

37

COX2 inhibitors?

Vioxx.

Non selective eg. paracetamol.

Trying to produce a drug that is more selective. 

38

TRPV1 antagonist?

  1. AMG 517
  2. First in human
  3. Multiple dose study
  4. Phase 1b

39

TRPV1 antagonist produce?

Life threatening increases in body temp in suspetible individuals.

 

40

Torcetrapib (Pfizer)

Cholesterol lowering drug.

Unacceptably high death rate. 

41

biomarkers?

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.

42

Translational biomarkers?

Represent common biological/biochemical measures

Efficacy, pharmacokinetic, safety, predictive

43

Phase 0 trials?

Studies performed on small patient numbers (10-15)

Provide early PoC in huumans.

Can test the pharmaceutics properties before.

44

Simple translational biomarkers?

In vitro and in vivo measure of cytokine release (proinflammatory and anti-inflammatory)

Use easily accessible fluid: eg. blood

45

Imaging techniques?

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.

46

MRI?

Non invasive structural imaging using magnetic resonance imaging.

47

Temporal MRI?

Efficacy of compounds tested

48

fMRI (functional magnetic resonance imaging)

Use of bimarkers.

MRI

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