U1 L2, L3 Drug Design & Stereochemistry Flashcards
What fraction of drug candidates prepared in a research lab actually gain a licence?
1/5000
What is meant by the term ‘novel molecule’ ?
A molecule previously unknown
What is meant by the term ‘lead compound’?
A chemical compound that shows promise as a treatment for disease and may lead to the development of a new drug
What are chemical drugs?
What is their approximate molecular weight?
What are they called when discovered?
Range from simple inorganic salts to complex organic molecules
Often referred to as ‘small molecules’ - molecular weight of <500
‘New Chemical Entity’, NCE
What are Biological Drugs?
What are they referred to when discovered?
AKA large molecule drugs e.g. proteins such as peptides or antibodies
‘New Biological Entity’, NBE
What are New Molecular Entities?
What newly discovered chemical and biological drugs are referred to when considered together
What is the average cost of bringing a new drug to the market?
£1.2 billion
Why are patents essential for drug development?
How long do patents last?
- give exclusive financial rights to inventors
- protect investment
- last 20 years
What is the normal minimum time it takes for a drug to go from discovery to licence?
15 years
How much does a ‘blockbuster drug’ earn per annum?
$1 billion +
What fraction of drugs that reach clinical trials fail them?
6/7
How long does the entire process of clinical trials generally take?
6 years
When in the drug development process should the drug be patented?
During discovery
Why do small molecule lead compounds often require optimisation?
Often do not have suitable properties to be used clinically
What is the FDA?
US Food & Drug Administration
In 2023, how many new drugs were approved by the FDA?
55
What sorts of conditions did the drug approvals made in 2023 focus on?
- infectious diseases e.g. COVID-19, pneumonia
- opioid use, abuse
- heart, blood, kidney, endocrine diseases
- lung diseases
- GI conditions
How many of the 55 drugs approved by the FDA in 2023 were first approved by the US to go on to be approved in other countries?
35
What are First-In-Class drugs?
How many of the 55 drugs approved by the FDA in 2023 were First-In-Class?
Drugs that have different mechanisms of action from existing therapies
20/55
What is the definition of a ‘natural product’ ?
Any discrete compound produced by a living organism
What percentage of the 877 small molecule NCEs introduced as drugs between 1981 and 2002 can be attributed to natural products?
61%
What is Paclitaxel used to treat?
Where is Paclitaxel isolated from?
Breast and ovarian cancer
From the bark of yew tree
What is Digoxin used to treat?
Where is it isolated from?
Heart failure, arrhythmias
Leaves of foxglove
What is Acetyl salicylic acid AKA?
Aspirin
What is the active ingredient in aspirin?
What is this a derivative of?
Salicin
Glucose derivative
Close derivatives of Artemisinin e.g. Artemether are currently licensed worldwide for what?
Malaria
Why is analogue synthesis of biochemicals and natural ligands from the body required to make a drug-like compound even though they can make good lead compounds anyway?
Natural ligand may
- have undesirable duration of action
- be excreted or metabolised too quickly
- may be chemically unstable
What does changing the structure of a compound allow for?
SAR - structure activity relationships
Why must analogues retain core structures?
To allow binding to the biological target
What is Salbutamol an analogue of?
Adrenaline
What is Methotrexate used for?
Anti-proliferative drug that blocks the effects of folic acid
Where did the first totally synthetic derived drugs originate from?
What are some examples of this?
British dye industry
Azo dyes - noted for antibacterial properties e.g. Phenazopyridine marketed as urinary antiseptic
What was the effect of adding a sulfonamide group to the azo-dye?
What was the use of the decomposed molecule?
Consequent compound had better antibacterial activity but decomposition to Sulfanilamide occurred in the bloodstream
Sulfanilamide is an excellent antibiotic
What led to the establishment of the FDA?
Death of 107 patients due to liver and kidney damage in 1937 due to the addition of 10% diethylene glycol to solubilise the Sulfanilamide
Why are sulfonamides now largely discontinued as antibiotics?
- side effects
- resistance
- more effective agents
What is Sulfadiazine still licensed for?
Rheumatic fever
What was the process of bringing Ibuprofen to market?
What type of lead compound was ibuprofen synthesised from?
- Chemists at Boots searching for better anti-inflammatory
- 650 total molecules screened - Ibufenac passed clinical trials but withdrawn as caused liver toxicity - jaundice
- Ibuprofen marketed in 1969, taking approx 20 years to develop
Synthetic lead compound
What is meant by ‘endogenous’ in terms of lead compounds?
Naturally occurring substance in the body
What is Tamiflu used for?
How was it synthesised?
Synthetic anti-viral drug; ethyl ester pro-drug allowing oral formulation
Via in silico drug design
- from Sialic acid lead compound; shown to interact with lead target enzyme
What does ‘in silico’ mean in terms of drug design?
Computer aided
How does Tamiflu interact with Neuraminidase (target enzyme) ?
COOH group interacts with 3x arginine side chains
(COOH group exposed when ester on Tamiflu is cleaved by plasma esterase enzymes)
What is meant by ‘me too’ drugs?
Has similar structure to existing drug, modified enough to make the compound novel but not so much that the activity is affected
Naproxen is a me-too drug based on what?
How does it compare to the original drug?
Ibuprofen
2x as potent, longer duration of action
What is a pharmacophore?
Portion of drug required for activity
What is an example of a drug causing side effects and leading to the synthesis of new drugs?
Sulfanilamide caused hypoglycaemia, led to development of tolbutamide for diabetes
What are 5 potential sources of lead compounds?
- Natural
- Endogenous
- Synthetic
- In silico design
- Me-too
What percentage of drugs are administered as mixtures?
25%
What is an enantiomer?
A pair of stereoisomers that are non-identical mirror images of each other
What are diastereoisomers?
A pair of non-identical stereoisomers that are not mirror images of each other
What is a meso compound?
A non-optically active stereoisomer (contains a plane of symmetry)
What are the most common drug targets?
What is important to consider about them?
Proteins e.g. receptors and enzymes
Often have chiral centres themselves
What are the two effects of the two enantiomers of thalidomide?
R-thalidomide - sedative (desired effect)
S-Thalidomide - teratogen; causes birth defects
Thalidomide is now back in use for what?
What must be considered for female patients taking thalidomide?
- bone marrow cancer (myeloma) treatment
- female patients MUST comply with a pregnancy prevention programme if taking Thalidomide or its analogues
What is an example of a Thalidomide analogue?
What is it used to treat?
Lenalidomide - also given as racemic mixture
Cancers
What does ADME stand for?
Absorption, Distribution, Metabolism and Excretion
What does R/S tell us about a chiral centre?
The groups around it and the positions in which they sit
Why is D/L used to describe chiral centres?
Classifies chiral centres with reference to a compound of glyceraldehyde
What does d/l or +/- tell us about chiral centres?
Classifies a molecule (that may contain more than one chiral centre) by the direction that it rotates polarised light
Clockwise = d (dextrorotatory)
Anti-clockwise = l (levorotatory)
influences drug suffix e.g. DEXTROmethorphan
RARELY USED TODAY, DOES NOT CORRELATE TO D/L
What two methods can be used to obtain pure chiral molecules?
- Chiral separation - physical method e.g. HPLC using chiral stationary phase
- Chiral pool - use a starting material that already contains a chiral centre
What are the disadvantages to using chiral separation to obtain a stereoisomer?
- impractical on large scales ie. Drug manufacture
- wasteful; 50% material thrown away
What is meant by ‘biosynthesis’ ?
Biosynthesis is often stereoselective - what does this mean?
Synthesis of molecules by a biological organism
Stereoselective - one enantiomer is formed in preference to the other
What is meant by ‘chiral pool’ ?
Name given to chiral molecules from nature that an be used as building blocks
Shikimic acid is derived from what natural product?
Why is it an important starting material?c
Star anise
It naturally contains three chiral centres
What is the word used to describe one isomer, in a pair of stereoisomers, with the greater activity?
eutomer
What is the word used to describe one isomer, in a pair of stereoisomers, with the lower activity?
distomer
what is the eudismic ratio?
the ratio of activity between the eutomer and ditomer of a pair of stereoisomers
Why is a significant proportion of propranolol dose inactive?
R-propranolol is 100x less active than S-propranolol
What is an anti-tussive?
cough reliever
Why is levomethorphan, the (-)isomer of dextromethorphan, not marketed despite its effects as an anti-tussive?
has all the side effects of opioids e.g. sedative and severe addiction
Why can stereoisomers of chiral drugs be transported differently into cells?
example?
trans-membrane proteins are chiral
e.g. the L-isomer of methotrexate is more readily absorbed than the D isomer
How are stereoisomers distributed via the blood differently?
(drugs transported via reversible binding to plasma proteins e.g. albumin)
Different stereoisomers will bind to plasma proteins with different affinities, though often small
Will the isomers in a pair of stereoisomers be metabolised the same, or differently?
differently
What do the differences in absorption, distribution and metabolism between a pair of stereoisomers mean for the mixture of isomers post-administration?
(a drug containing chiral centres) will rarely exist as an equal mixture
What are the advantages to preparing and marketing a single enantiomer as a new drug as opposed to discovering and developing a brand new drug?
potentially cheaper and quicker
What is the chiral switch?
the development of a single isomer drug from a previously marketed racemate
What are some advantages to using single-isomer drugs over racemates?
- improved biological activity
- modified dosage
- reduced side effects
Ibuprofen is administered as a racemate. In terms of activity, how can the R and S isomers be described?
How does the proportion of R and S isomers change post-administration?
R-isomer is inactive
S-isomer inhibits cyclooxygenase
post-administration approx 60% R-isomer is converted to S-isomer by enzymic chiral inversion
What is the clinical name for the S-isomer of ibuprofen?
How effective is it compared to ibuprofen?
What are the indications for Dexibuprofen, marketed as Seractil (POM) ?
Dexibuprofen
is as effective at half the dose (therefore twice as potent)
pain and inflammation associated with osteoarthritis, dysmenorrhea, dental pain
What is Ki as a constant?
What does a high value indicate?
inhibitor constant - indication of how potent an inhibitor is
A high value indicates less inhibition e.g. of an enzyme
Why is levocetirizine (R-isomer of cetririzine), administered at a lower dose than the racemic cetirizine?
levocetirizine targets H1 histamine receptor at Ki = 3.2 nM
cetirizine targets H1 histamine receptor at Ki = 6.3nM (less potent an inhibitor)
Why is the S-isomer of Bupivacaine (levo-//), preferred over a Bupivacaine racemate?
Bupavacaine used for spinal anaesthesia
R-Bupavacaine is more active but cardiotoxic
S-Bupavacaine has anaesthetic and analgesic properties similar to racemate but with fewer adverse effects
