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PH2114 Principles Of Drug Design And Disposition > U1 L2, L3 Drug Design & Stereochemistry > Flashcards

U1 L2, L3 Drug Design & Stereochemistry Flashcards

1
Q

What fraction of drug candidates prepared in a research lab actually gain a licence?

A

1/5000

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2
Q

What is meant by the term ‘novel molecule’ ?

A

A molecule previously unknown

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3
Q

What is meant by the term ‘lead compound’?

A

A chemical compound that shows promise as a treatment for disease and may lead to the development of a new drug

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4
Q

What are chemical drugs?

What is their approximate molecular weight?

What are they called when discovered?

A

Range from simple inorganic salts to complex organic molecules

Often referred to as ‘small molecules’ - molecular weight of <500

‘New Chemical Entity’, NCE

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5
Q

What are Biological Drugs?

What are they referred to when discovered?

A

AKA large molecule drugs e.g. proteins such as peptides or antibodies

‘New Biological Entity’, NBE

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6
Q

What are New Molecular Entities?

A

What newly discovered chemical and biological drugs are referred to when considered together

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7
Q

What is the average cost of bringing a new drug to the market?

A

£1.2 billion

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8
Q

Why are patents essential for drug development?

How long do patents last?

A
  • give exclusive financial rights to inventors
  • protect investment
  • last 20 years
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9
Q

What is the normal minimum time it takes for a drug to go from discovery to licence?

A

15 years

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10
Q

How much does a ‘blockbuster drug’ earn per annum?

A

$1 billion +

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11
Q

What fraction of drugs that reach clinical trials fail them?

A

6/7

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12
Q

How long does the entire process of clinical trials generally take?

A

6 years

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13
Q

When in the drug development process should the drug be patented?

A

During discovery

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14
Q

Why do small molecule lead compounds often require optimisation?

A

Often do not have suitable properties to be used clinically

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15
Q

What is the FDA?

A

US Food & Drug Administration

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16
Q

In 2023, how many new drugs were approved by the FDA?

A

55

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17
Q

What sorts of conditions did the drug approvals made in 2023 focus on?

A
  • infectious diseases e.g. COVID-19, pneumonia
  • opioid use, abuse
  • heart, blood, kidney, endocrine diseases
  • lung diseases
  • GI conditions
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18
Q

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?

A

35

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19
Q

What are First-In-Class drugs?

How many of the 55 drugs approved by the FDA in 2023 were First-In-Class?

A

Drugs that have different mechanisms of action from existing therapies

20/55

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20
Q

What is the definition of a ‘natural product’ ?

A

Any discrete compound produced by a living organism

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21
Q

What percentage of the 877 small molecule NCEs introduced as drugs between 1981 and 2002 can be attributed to natural products?

A

61%

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22
Q

What is Paclitaxel used to treat?

Where is Paclitaxel isolated from?

A

Breast and ovarian cancer

From the bark of yew tree

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23
Q

What is Digoxin used to treat?

Where is it isolated from?

A

Heart failure, arrhythmias

Leaves of foxglove

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24
Q

What is Acetyl salicylic acid AKA?

A

Aspirin

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25
Q

What is the active ingredient in aspirin?

What is this a derivative of?

A

Salicin

Glucose derivative

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26
Q

Close derivatives of Artemisinin e.g. Artemether are currently licensed worldwide for what?

A

Malaria

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27
Q

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?

A

Natural ligand may
- have undesirable duration of action
- be excreted or metabolised too quickly
- may be chemically unstable

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28
Q

What does changing the structure of a compound allow for?

A

SAR - structure activity relationships

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29
Q

Why must analogues retain core structures?

A

To allow binding to the biological target

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30
Q

What is Salbutamol an analogue of?

A

Adrenaline

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31
Q

What is Methotrexate used for?

A

Anti-proliferative drug that blocks the effects of folic acid

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32
Q

Where did the first totally synthetic derived drugs originate from?

What are some examples of this?

A

British dye industry

Azo dyes - noted for antibacterial properties e.g. Phenazopyridine marketed as urinary antiseptic

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33
Q

What was the effect of adding a sulfonamide group to the azo-dye?

What was the use of the decomposed molecule?

A

Consequent compound had better antibacterial activity but decomposition to Sulfanilamide occurred in the bloodstream

Sulfanilamide is an excellent antibiotic

34
Q

What led to the establishment of the FDA?

A

Death of 107 patients due to liver and kidney damage in 1937 due to the addition of 10% diethylene glycol to solubilise the Sulfanilamide

35
Q

Why are sulfonamides now largely discontinued as antibiotics?

A
  • side effects
  • resistance
  • more effective agents
36
Q

What is Sulfadiazine still licensed for?

A

Rheumatic fever

37
Q

What was the process of bringing Ibuprofen to market?

What type of lead compound was ibuprofen synthesised from?

A
  1. Chemists at Boots searching for better anti-inflammatory
  2. 650 total molecules screened - Ibufenac passed clinical trials but withdrawn as caused liver toxicity - jaundice
  3. Ibuprofen marketed in 1969, taking approx 20 years to develop

Synthetic lead compound

38
Q

What is meant by ‘endogenous’ in terms of lead compounds?

A

Naturally occurring substance in the body

39
Q

What is Tamiflu used for?

How was it synthesised?

A

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

40
Q

What does ‘in silico’ mean in terms of drug design?

A

Computer aided

41
Q

How does Tamiflu interact with Neuraminidase (target enzyme) ?

A

COOH group interacts with 3x arginine side chains

(COOH group exposed when ester on Tamiflu is cleaved by plasma esterase enzymes)

42
Q

What is meant by ‘me too’ drugs?

A

Has similar structure to existing drug, modified enough to make the compound novel but not so much that the activity is affected

43
Q

Naproxen is a me-too drug based on what?

How does it compare to the original drug?

A

Ibuprofen

2x as potent, longer duration of action

44
Q

What is a pharmacophore?

A

Portion of drug required for activity

45
Q

What is an example of a drug causing side effects and leading to the synthesis of new drugs?

A

Sulfanilamide caused hypoglycaemia, led to development of tolbutamide for diabetes

46
Q

What are 5 potential sources of lead compounds?

A
  1. Natural
  2. Endogenous
  3. Synthetic
  4. In silico design
  5. Me-too
47
Q

What percentage of drugs are administered as mixtures?

A

25%

48
Q

What is an enantiomer?

A

A pair of stereoisomers that are non-identical mirror images of each other

49
Q

What are diastereoisomers?

A

A pair of non-identical stereoisomers that are not mirror images of each other

50
Q

What is a meso compound?

A

A non-optically active stereoisomer (contains a plane of symmetry)

51
Q

What are the most common drug targets?

What is important to consider about them?

A

Proteins e.g. receptors and enzymes

Often have chiral centres themselves

52
Q

What are the two effects of the two enantiomers of thalidomide?

A

R-thalidomide - sedative (desired effect)

S-Thalidomide - teratogen; causes birth defects

53
Q

Thalidomide is now back in use for what?

What must be considered for female patients taking thalidomide?

A
  • bone marrow cancer (myeloma) treatment
  • female patients MUST comply with a pregnancy prevention programme if taking Thalidomide or its analogues
54
Q

What is an example of a Thalidomide analogue?

What is it used to treat?

A

Lenalidomide - also given as racemic mixture

Cancers

55
Q

What does ADME stand for?

A

Absorption, Distribution, Metabolism and Excretion

56
Q

What does R/S tell us about a chiral centre?

A

The groups around it and the positions in which they sit

57
Q

Why is D/L used to describe chiral centres?

A

Classifies chiral centres with reference to a compound of glyceraldehyde

58
Q

What does d/l or +/- tell us about chiral centres?

A

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

59
Q

What two methods can be used to obtain pure chiral molecules?

A
  1. Chiral separation - physical method e.g. HPLC using chiral stationary phase
  2. Chiral pool - use a starting material that already contains a chiral centre
60
Q

What are the disadvantages to using chiral separation to obtain a stereoisomer?

A
  • impractical on large scales ie. Drug manufacture
  • wasteful; 50% material thrown away
61
Q

What is meant by ‘biosynthesis’ ?

Biosynthesis is often stereoselective - what does this mean?

A

Synthesis of molecules by a biological organism

Stereoselective - one enantiomer is formed in preference to the other

62
Q

What is meant by ‘chiral pool’ ?

A

Name given to chiral molecules from nature that an be used as building blocks

63
Q

Shikimic acid is derived from what natural product?

Why is it an important starting material?c

A

Star anise

It naturally contains three chiral centres

64
Q

What is the word used to describe one isomer, in a pair of stereoisomers, with the greater activity?

A

eutomer

65
Q

What is the word used to describe one isomer, in a pair of stereoisomers, with the lower activity?

A

distomer

66
Q

what is the eudismic ratio?

A

the ratio of activity between the eutomer and ditomer of a pair of stereoisomers

67
Q

Why is a significant proportion of propranolol dose inactive?

A

R-propranolol is 100x less active than S-propranolol

68
Q

What is an anti-tussive?

A

cough reliever

69
Q

Why is levomethorphan, the (-)isomer of dextromethorphan, not marketed despite its effects as an anti-tussive?

A

has all the side effects of opioids e.g. sedative and severe addiction

70
Q

Why can stereoisomers of chiral drugs be transported differently into cells?

example?

A

trans-membrane proteins are chiral

e.g. the L-isomer of methotrexate is more readily absorbed than the D isomer

71
Q

How are stereoisomers distributed via the blood differently?

A

(drugs transported via reversible binding to plasma proteins e.g. albumin)
Different stereoisomers will bind to plasma proteins with different affinities, though often small

72
Q

Will the isomers in a pair of stereoisomers be metabolised the same, or differently?

A

differently

73
Q

What do the differences in absorption, distribution and metabolism between a pair of stereoisomers mean for the mixture of isomers post-administration?

A

(a drug containing chiral centres) will rarely exist as an equal mixture

74
Q

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?

A

potentially cheaper and quicker

75
Q

What is the chiral switch?

A

the development of a single isomer drug from a previously marketed racemate

76
Q

What are some advantages to using single-isomer drugs over racemates?

A
  • improved biological activity
  • modified dosage
  • reduced side effects
77
Q

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?

A

R-isomer is inactive
S-isomer inhibits cyclooxygenase

post-administration approx 60% R-isomer is converted to S-isomer by enzymic chiral inversion

78
Q

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) ?

A

Dexibuprofen

is as effective at half the dose (therefore twice as potent)

pain and inflammation associated with osteoarthritis, dysmenorrhea, dental pain

79
Q

What is Ki as a constant?

What does a high value indicate?

A

inhibitor constant - indication of how potent an inhibitor is

A high value indicates less inhibition e.g. of an enzyme

79
Q

Why is levocetirizine (R-isomer of cetririzine), administered at a lower dose than the racemic cetirizine?

A

levocetirizine targets H1 histamine receptor at Ki = 3.2 nM
cetirizine targets H1 histamine receptor at Ki = 6.3nM (less potent an inhibitor)

80
Q

Why is the S-isomer of Bupivacaine (levo-//), preferred over a Bupivacaine racemate?

A

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

PH2114 Principles Of Drug Design And Disposition (3 decks)

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