Chirality in Drug Design (DONE)

Question 1

Chirality of chloramphenicol

Answer 1

Chloramphenicol, antibiotic frequently used for eye infections has two chiral centres
Of the four stereoisomers, the RR form is the most biologically active
The term diastereoisomer is often shortened to diastereomer

Question 2

What is a racemic mixture?

Answer 2

Racemate/ racemic mixture: could consider a racemic drug as being 50% impure (or more if diastereoisomer)
Traditional view is to try and avoid drugs with chiral centres- mode of action, manufacturing difficulties, expense
Although, when chiral centres are present, they are usually marketed as the racemate e.g. atenolol, salbutamol

Question 3

Chirality of excipients

Answer 3

Many excipients are chiral too
Despite widespread use of these excipients, very little research on:
Stereochemical issues that could affect (good or bad) Pharmaceutical properties

Question 4

Solid formulations of chiral drugs

Answer 4

Enantiomeric crystals, racemic crystals, pseudo-racemic crystals
The chiral crystal properties of a solid dosage form (including excipients) can affect:
Solubility (single enantiomer ketoprofen is twice as soluble as racemic drug)
Release rate
Potency

Question 5

What is the main PK difference from stereoisomers?

Answer 5

Differences in drug distribution can occur due to stereoselective binding to plasma proteins

Question 6

Other Stereochemical differences

Answer 6

Transdermal delivery- a difference in skin absorption between enantiomers has been recorded for some drugs. The S-enantiomer of propranolol penetrates skin more readily
Whenever you consider the properties of molecules containing chiral centres, you have to assume that each enantiomer will behave differently

Question 7

Eutomers and distomers

Answer 7

For any drug with stereoisomers, the eutomer is the isomer with the greatest biological activity and the distomer(s) is/are the isomer(s) that have lower activity

Question 8

What is the eudismic ratio?

Answer 8

Eudismic ratio = activity of the distomer/ activity of the eutomer

Question 9

What is Pfeiffer’s rule?

Answer 9

In a series of chiral compounds the eudismic ratio increases with increasing potency of the eutomer (drugs effective at low doses tend to have the greatest eudismic ratio)

Question 10

What is the rocking tetrahedron?

Answer 10

A two point model that helps to explain why in some cases a chiral drug shows equal activity for both enantiomers
When only two drug-target interactions are required for activity both enantiomers can potentially bind i.e. equal activity
This implies there are no strong interactions with X and Y so these groups are free to move

Question 11

The Chiral Switch

Answer 11

The eudismic ratio of a molecule can be exploited by the chiral switch or the de novo design of chiral drugs
Chiral switch was initially welcomed as a way to improve racemic drugs and was only practical for old drugs

Question 12

Criticisms of the chiral switch

Answer 12

Do they really have a clinical difference that the patient perceives?
Merely line extensions of existing products and or patents?
Marketing- chiral switch products are introduced just before racemate patent expires blocking competition from generic manufacturers
Today, license applications require all enantiomers to be synthesized and screened, decide (evidence based) to manufacture a new drug as a racemate or the de novo synthesis of the most active single isomer

Question 13

Chiral switch: antihistamines

Answer 13

H1 receptor antagonists are highly effective against a range of allergies
Chlorphenamine has one chiral centre and is administered as a racemate
R isomer has higher clearance
Cetirizine administered as a racemate, chrial switch to levocetirizine
High eudismic ratio favours chiral switch

Question 14

Chiral switch: salbutamol

Answer 14

Salbutamol is a bronchodilator, an agonist of the B-adrenoceptor and an important treatment for asthma
Salbutamol increases airway diameter without CV-side effects e.g. increase in heart rate, normally administered as a racemate
USA only- chiral switch to levabuterol

Question 15

Chiral switch: omeprazole

Answer 15

Omeprazole launched in 1988 by Astra, EU patent expired 1999
Some evidence that the S isomer has a better pharmacodynamic profile, chiral switch marketed as esomeprazole from 2000, based on evidence
Generic racemic omeprazole is much cheaper, AstraZeneca accused of evergreening

Question 16

Chiral switch: citalopram

Answer 16

Citalopram approved in 1998 and escitalopram in 2002
Data suggests this is a beneficial chiral switch, whereas it was not for fluoxetine, another SSRI
Both have similar PK, dosing is lower with escitaolpram, controversy still surrounds the effect that the patient perceives

Question 17

Marketing of clopidogrel

Answer 17

Newer drugs tend to be marketed from outset as a single enantiomer, e.g. clopidogrel
Under the trade name Plavix it was sold as the single enantiomer, the racemate has never been sold
Was the worlds second highest gross income drug, patent now expired

Question 18

How are chiral drugs made?

Answer 18

Chiral resolution- make the racemate, then separate enantiomers, traditional method not used widely today
Chiral starting materials- the chiral pool
Asymmetric synthesis- creating chirality during production/ synthesis of the drug

Question 19

Chiral resolution

Answer 19

Pairs of diastereoisomers have different physiochemical properties (enantiomers do not) so can be separated e.g. by recrystallization and chromatography

Question 20

Use of chiral starting materials

Answer 20

The synthesis of clopidogrel is straightforward and produces a racemate
Industrial preparation uses chiral starting material
Cheaper to obtain chiral starting material rather than resolve at the end as this would waste 50% of the manufactured material

Question 21

How are chiral drugs made?

Answer 21

Epichlorohydrin is a bulk industrial chemical (cheap) and is a precursor to the functional group common in beta blockers and other drugs
50:50 chance of reaction on either side of the epoxide, gives a racemate
Racemates can often be separated, but it is hard, expensive and inefficient

Question 22

Stereoselective synthesis

Answer 22

Chiral centres can be synthesized under certain very specific conditions
Chiral epoxides are useful because they give access to chiral alcohols- a very common functional group in drugs

Question 23

Stereoselective synthesis: esomeprazole

Answer 23

Sharpless (inventor) conditions can be used for chiral oxidations e.g manufacture of esomeprazole

Question 24

Enzymes in stereosynthesis

Answer 24

The chiral properties of enzymes can be used in synthesis
Lipases hydrolyse fatty esters and are a type of esterase- chirality of this reaction is not obvious, consider the chiral switch of atenolol- lipase only hydrolyses one of the enantiomers

Question 25

Other chiral atoms

Answer 25

Chirality with atoms other than carbon is possible- the definition of an atom with four different groups attached, can be applied to atoms other than C

Question 26

Chiral Phosphorous

Answer 26

Sovaldi- fastest selling drug ever (hepatitis C)
Chiral, 6 centres, 64 possible isomers, however four chiral centres are natural (occur in amino acids/ nucleosides)
Chiral centres in natural configuration are from chiral pool
One of the remaining chiral centres is easy to synthesize as neighbouring chiral centres influence synthesis
Chiral P is very hard to resolve, so administered as a 50:50 mixture of the two diastereoisomers

Question 27

Chiral sulphur

Answer 27

Modafinil (narcolepsy)- chiral switch, armodafinil approved by FDA in 2007 for same indication, but declined an application in 2010 for use to prevent jet lag

Question 28

Intellectual property

Answer 28

Patents are legal contracts awarded to individuals or corporations to protect their inventions
Grant a monopoly for a fixed time period, usually 20 years
The invention must be unobvious- not capable to the average skilled person in possession of relevant prior art
Prior art is the public knowledge that could be relevant to the invention before the priority date (date patent filled)

Question 29

Geometric stereoisomers

Answer 29

Natural products are known for their rich stereochemistry, the cinchona tree produces the pseudoenantiomers quinine and quinidine
It is postulated that quinine could undergo a chiral switch to the diastereoisomer
Similarity to quinidine suggests that it should have potential for cardiovascular indications

Question 30

Geometric enantiomers

Answer 30

Gossypol is a natural product
1970s- Chinese researchers established link between male infertility and cooking using cottonseed oil
Gossypol identified to be responsible, furthermore activity resided in the (-) isomer could have provided novelty
Trialed as male contraceptive pill but serius side effects stopped research- hypokalaemia