Week 4 Part 2 Flashcards
What are examples of single-enantiomer drugs?
- Lipitor (atorvastatin calcium)
- Plavix (clopidogrel bisulphate)
- Nexium (esomeprazole magnesium)
What is the total sales of single-enantiomer drugs ?
$30 billion
Mirror image of the drug
Not going to interact with the protein target
Biologically inactive or less active
Many biological targets
Going to be drug-specific in their interactions
What can isomers be divided into?
- Constitutional/structural isomers
2. Stereoisomers
What are stereoisomers divided into?
- Configurational isomers
2. Conformational isomers
What can conformation isomers of stereoisomers be divided into?
- Rotamers
- Atropisomers
- Ring inversion isomers
What can configurational isomers of stereoisomers be divided into?
- Diastereomers
2. Enantiomers
What can Diastereomers be divided into?
- Cis/trans-isomers
2. Diastereomers containing a chiral centre
Define isomers
Different compounds with same chemical formula
Constitutional isomers
Very little relevance to us
Same chemical constitution and they can be different molecules
What does isomers have?
- Same functional groups
2. Different physical and chemical properties
What can stereoisomers be separated into?
- Diastereomers
2. Enantiomers
Why are Diastereomers very common in chemistry?
Same chemical groups
Define stereoisomers
Compounds with the same chemical group connections
Different arrangement in space
Define Diastereomers
Stereoisomers that are not mirror images
Different chemical compounds
Different physical properties
Conformers and Rotamers
Very little importance
Have unstable structures
Define Enantiomers
Stereoisomers that are non superimposable mirror images
Differ only in their optical activity/direction of optical rotation
Define chirality
Geometric property of some molecules where a chiral molecule is not superimposable on its mirror image
What creates a chiral centre?
Chiral carbon atom or asymmetric carbon atom that is bonded to 4 different groups creating a chiral centre
What are different forms of chirality called?
Enantiomorph
Enantiomorph
A chiral centre results in two possible structures which are mirror images of each other
What is optical activity?
The ability to rotate the plane of polarised light
What can chirality be described at?
In terms of absolute configuration which defines the geometry of the molecule and the relationship with its ability to rotate polarised light
What is polarineter?
A device or equipment for measuring the degree of rotation of polarised light and therefore the chirality of enantiomers
What is Racemic Mixture?
Equal quantities of enantiomers
No optical activity
What is the basic principle of polarimetry?
- Have focused polarised light in filter
- Shine light through sample chamber
- Measure the level of reflection
Polarimetry - rotates clockwise
Dextrorotatory (+ or d)
Polarimetry - rotates counter clockwise
Levorotatory (-, I)
What is the physicochemical properties of enantiomers?
- Same boiling point
- Same melting point
- Same density
- Same refractive index
- Rotate the plane of polarised light to the same magnitude but in opposite directions
What is biological discrimination?
- Active site of enzymes and receptors generally selective for a specific enantiomers
What are examples of biological discrimination?
- Taste buds
- Scent receptors
Show chiral discrimination
What may enantiomers have?
Different smells
D-limonene - citrus/orange skins
L-limonene - turpentine odour
The history of molecule - 1848
Pasteur achieves the first optical resolution of the (+) and (-) of tartaric acid
The history of molecule - 1891 -1900
Fischer Projection
A two-dimensional representation of three-dimensional organic molecules originally proposed for depiction of carbohydrates
The history of Molecule - 1951-1966
Cahn-Ingold-Prelog (CIP)
Priority rules
What is the limitation of Fischer Projection?
Doesn’t really tell you much about the structure of a molecule
What is the Fischer Projection?
The penultimate group of the molecule defines whether D or L form depending on whether the hydrogen is on the left or right
Penultimate carbon of D-sugars
Hydrogen in left
Hydroxyl on the right
What does the D- and L1 nomenclature relate to?
Whether the hydroxyl is drawn on the right or left
What is Fischer Projection not based on?
Any measure of optical activity
What is the D- and L- system of Fischer Projection used for?
- Sugars
2. Amino acids
Naturally occurring sugars
D-
Naturally occurring amino acids
L-
What is glycine?
- Achiral
What are the 19 amino acids occurring naturally?
L-amino acids
How does the CIP naming system work?
- 4 groups aroubd a chiral centre are prioritised according to atomic number. The highest atomic number is assigned priority 1 and the lowest atomic number is assigned priority 4
- If two or more of the atoms are attached to chiral centre are the same then outward exploration is necessary to identify the group with highest atomic number
- A clockwise decreasing order is assigned (R)-configurational and anti clockwise decreasing order is assigned (S)-configuration
What is biological discrimination important for?
Protein-target recognition
What is Ephedrine?
Natural molecule that is being used for centuries in medicine
Traced back to Chinese medicine
Sympathomimetic amine stimulates the release of noradrenaline from the sympathetic nerve terminals
Traditional use in anti-asthmatics
What are 2 active form of isomers?
- Ephedrine
2. Pseudoephedrine
Why was pseudoephedrine banned?
Causes hypertension
What are examples of Racemic drugs with equally bioactive enantiomers?
- Anti-cancer drug e.g. cyclophosphamide
2. Antidepressant e.g. fluoxetine
Unidirectional: what is active?
- S-ibuprofen
What is R-ibuprofen converted into?
S- by hepatic enzymes
What Racemic drug undergo chiral inversion?
Bidirectional:
- 3-hydroxybenzodiazepine
E.g. lorazepam and temazepam
What are 3 examples which illustrate a problem in terms of using a Racemic mixture as a therapeutic product?
- Citalopram
- Methadone
- Warfarin
What is Citalopram?
Antidepressant
What is methadone used as?
Opioid
Provide pain relief
Main therapeutic use is to give to addict to wheel off the opioids
Methadone
Reversal of addiction
Long action
What enantiomers is the most active?
S-warfarin
R(-) methadone
Opioid
S (+) methadone
Inhibits hERG
Potassium channel
Prolonged QT interval
Torsades de pointes
What is the active isomer of citalopram?
Escitalopram
What is the pharmacokinetic of stereochemistry?
- Absorption
- Distribution
- Metabolism
- Elimination
What can enantiomers have?
Identical efficacy and toxicity
What can one enantiomer possess?
Much greater pharmacological activity
What can one enantiomer have?
Less pharmacological activity and similar or greater toxicological effects
What are majority of Racemic drugs absorbed by?
Passive diffusion which has no stereoselectictivity
What does plasma protein binding have a key influence on?
- Tissue distribution
- Pharmacological properties
- Merabolism/elimination
What may enantiomers show?
- Stereoselectivity for protein binding
R (+) propanolol
- High albumin binding
- High rate of metabolism
- Low plasma concentration
- Less potent as a beta-blocker
S (-) propranolol
- Highly bound to alpha1-acid glycoprotein
- Slower metabolism
- 60-100 times more potent as a beta-blocker
What is common?
Stereoselective metabolism of drugs
Warfarin
- Exceptionally complex
- Affected by genetic polymorphism
- Wide inter-individual variation in dose response and frequent bleeds
What is the most active enantiomer of warfarin?
S-warfarin
What is S-warfarin metabolised by?
CYP2C9
What is R warfarin metabolised by?
3 different CYPS
How does warfarin work?
Inhibits the enzyme that is involved with vitamin K
Involved in changes in glutamate side chains of these coagulation factors
What is a real risk of overdose/toxic consequence of methadone consumption?
Bigger concentration of opioid depressing activity and cardiotoxic metabolite
Thalidomide
- Sold as Racemic mixture from 1957-1961
- Used to treat morning sickness until birth defects were known
- R-enantiomer is sedative (desired effect)
- S-enantiomer is teratogenic or the source of ateratogenic metabolite (mechanism never fully define)
- In Vivo conversion of R- into S- so no safe isomer
What is Omeprazole?
- The first proton pump (H+, ATPase) inhibitor for treatment of gastric acid-related disease
- Primarily metabolised by polymorphically expressed cytochrome P450 - CYP2C19.1
Esomeprazole
Metabolised to a lesser extent by CYP2C19 than R-Omeprazole
Metabolised at a lower rate
Higher plasma levels
What does S-enantiomer of Omeprazole inhibit?
CYP2C19
What can pure enantiomers be?
- Safe
2. More effective drugs
What is an example of 50/50 Racemic ?
- Formoterol
2. Salmeterol
What is the advantage of Enantiopure?
- Greater pharmacological efficacy
2. Reduced side effects
What are the 2 main strategies for preparation of enantiopure compounds?
- Chiral Resolution
2. Asymmetric synthesis
What is chiral resolution?
Synthesis as a racemate
Followed by separation of the enantiomers
What is asymmetric synthesis?
- Use of chiral starting materials, chiral catalyst and the application of asymmetric induction
- Enzymes (biocatalyst) may be hard to produce the desired compound or chiral intermediate
- Enantioconvergent synthesis - the desired enantiomer is synthesised from a Racemic precursor molecule
