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4117- T > Metabolism And Toxicology > Flashcards

Metabolism And Toxicology Flashcards

1
Q

What makes a good lead compound

A

Good target interactions
Good PK
Good pharmaceutics
Novelty

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2
Q

Why is it important to have an understanding of met and tox?

A

To assess possible limitations to improve the properties of the drug

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3
Q

How can you improve drug characteristics?

A

Pro drug approach
Block metabolism
Improve delivery
Design out toxixity

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4
Q

What is a novel drug?

A

Innovative product that serves unmet medical needs or significantly helps advance patient care and public health.

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5
Q

What is an NME?

A

Have chemical structures which have never been approved before

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6
Q

What happens during Phase 1 of metabolism

A

mainly oxidation reactions, occurs in the liver by cyp450 mono-oxygenase enzymes

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7
Q

What happens during Phase 2 of metabolism

A

conjugation reactions- drugs are conjugated with water soluble groups to aid urinary and biliary excretions

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8
Q

Types of P1 metabolism

A

aromatic/aliphatic hydroxylation, N&O de-methylation, amide hydrolysis, epoxidation, ester hydrolysis, amine oxidation, nitro-reduction

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9
Q

What happens during epoxidation?

A

double bond is broken, oxygen group becomes attached to each carbon

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10
Q

What happens during amide hydrolysis

A

amide bond is hydrolysed, results in the formation of a carboxylic acid and an amine.

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11
Q

where is amide hydrolysis the fastest and slowest?

A

fastest in the liver, slower in the stomach

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12
Q

What happens during nitro reduction?

A

production of toxic intermediates (nitroso groups), by hepatic reductases

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13
Q

What are the types of oxidation reactions?

A

aliphatic and aromatic hydroxylation, epoxidation and N&O de-methylation

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14
Q

What is the most common reaction of phase 2 metabolism

A

Glucoronodation- glucoronic acid group is conjugated to drug to increase the solubility

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15
Q

what can occur during phase 2 metabolism

A

glucoronidation, sulphate conjugation and aromatic carboxylic acids conjugated with glycine

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16
Q

what happens during sulphate conjugation

A

sulphate group is added to N or O of a compound.

17
Q

what happens during aromatic carboxylic acids conjugated with glycine

A

removal of OH group of carboxylic acid, addition of primary amide

18
Q

what should be considered when anticipating Phase 2 reactions

A

polar conjugation could result in the drug being excreted too rapidly (reduce t1/2)
important not to block any important hydrogen bonding sites as this can lead to drug accumulation

19
Q

What methods are used to predict toxicology

A
  • Binding assays -wet screening (measures the interaction between two molecules)
  • Off target in silico screening- virtual kinase library (screen similar drug candidates to infer off target effects)
  • structural alerts (identify functional groups that are likely to cause toxicity)
  • Metabolomics- Urine analysis (study of small molecules within cells, tissues and organs)
20
Q

toxicology of- nitro-aromatics and anilines

A
  • metabolised into Nitroso groups= toxic

- nitroso group reacts with proteins and nucleic acids to form covalent adducts

21
Q

toxicology of- quinones

A

v toxic
very reactive to nucleophiles
(example= paracetamol toxicity- 15% is metabolised to quinones in the liver, this accumulates and causes liver damage)

22
Q

toxicology of- alkyl halides

A
  • I>B>F
  • react with nucleophiles
  • not aromatic halides
23
Q

toxicology of- carboxylic acids

A
  • metabolised to acetylglucuronides which are chemically stable
  • these reach high concentrations in the plasma and undergo ester hydrolysis producing glucuronic acid whi h will irreversibly bind to proteins and nucleic acid
24
Q

toxicology of- Michael Acceptors

A

react with nucleophiles and form adducts that detoxifies the michael acceptors

25
Q

What is a bioisostere?

A

function group (s) of similar properties and shape

26
Q

Bioisostere of H

A

F

C-F bond is stronger than C-H bond and cannot be broken easily

27
Q

Bioisostere of CH3

A

CL

CL atom cannot be easily oxidised

28
Q

Bioisostere of Nitro’s

A

Trifluro-methyl, cyanide and lactone (cyclic ester)

29
Q

Bioisostere of Amines

A

Methyl and hydroxy

similar shapes but don’t mimic basicity

30
Q

Bioisostere of COOH (ph~5)

A

tetrozole (Ph=4.9) and 2,4-diflurohenol(Ph= 6)

Tetrozole= better as similar shape and mimics acidity

4117- T (6 decks)

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