WEEK 3

Question 1

What is a Prodrug ?

Answer 1

Inactive compound converted to an active drug in the body

Question 2

What is an example of a Prodrug and its use ?

Answer 2

For example, Parkinson’s disease is related to a lack of dopamine in the brain.
- Dopamine is too polar to cross the blood brain barrier (BBB) so Levodopa is used.
- Levodopa uses a carrier protein to cross the BBB and then is decarboxylated by a
decarboxylase enzyme generating active dopamine in the brain.

Question 3

What can act as a prodrug to nordazepam ?

Answer 3

Valium may act as a prodrug to nordazepam. The latter has a short duration of action when administered, so the use of Valium leads to sustained action

Question 4

Is Aspirin a prodrug ? explain what is hydrolysed ?

Answer 4

• Aspirin is a prodrug; the ester is hydrolysed in the stomach to a phenol derivative.
• The latter, when used, gives rise to gastric bleeding.

Question 5

What happens to the action of Fluphenazine ?

Answer 5

• The action of the antipsychotic drug Fluphenazine is prolonged by using lipophilic (fatty ester)
• The ester derivative is injected intramuscularly and will slowly diffuse into the blood and be hydrolysed to the active analogue

Question 6

What can subtle difference in size/shape/conformation of the drug affect ?

Answer 6

Drugs can bind to biological receptors or enzymes; subtle differences in size/shape/conformation of the drug can affect binding.

Question 7

How do “floppy molecules” bind and why ?

Answer 7

“Floppy” molecules have many degrees of freedom and bind less tightly to receptor or enzyme

Question 8

High energy “active” conformation may ?

Answer 8

Be stabilised with conformational restriction. Drug can “lock” onto receptor or enzyme

Question 9

What can add conformation restriction ?

Answer 9

Further ring adds conformational restriction

Question 10

What is Metoclopramide ?

Answer 10

• A dopamine receptor (D2) antagonist with anti-emetic and prokinetic properties (5HT3 antagonist).
• Cocaine has 5HT effects.

Question 11

What is increased 5HT3 antagonism used for ?

Answer 11

Used to treat nausea during chemotherapy.

Question 12

What is Bioisosteres ?

Answer 12

Exchange of an atom or group with a similar atom/group with similar biological properties

Question 13

A lead compound may have good affinity but ?

Answer 13

Have problems in terms

of bioavailability, toxicity or metabolism

Question 14

So bioisosterism is used to?

Answer 14

Improve lead quality- lead optimisation

Question 15

What is Fluorine a classic replacement for ?

Answer 15

Fluorine is a classical replacement for H (isostere); similar size but blocks P450 metabolism

Question 16

When should you prevent using fluorine in medicinal chemistry ?

Answer 16

Prevent in vivo racemisation

Question 17

What are some functions of Fluorine in Medicinal chemistry?

Answer 17

• Lower pKa of amines, electron withdrawing group (EWG)
• Block metabolism
• Improve affinity -
  C-F can form weak H bonds and good for electrostatic interactions e.g. C-F——C(=O), C-F—C-H

Question 18

Explain what happens when you replace OCH2 in Propranolol ?

Answer 18

• Replacing OCH22 with CH=CH, SCH, CH2CH2 eliminates activity
• Replacing OCH2 with NHCH2 retains activity
• Implies O involved in binding (HBA)

Question 19

Explain the Dermorphin Analogues ?

Answer 19

• Peptides have poor bioavailability so are not usually good drugs.
• They can be cleaved by peptidases.
• Replacing amino acid, amide bond or add conformational restraint will improve drug-likeness.
• 1,2,4-oxadiazole is a useful peptide surrogate

Question 20

What are Integrins ?

Answer 20

Surface receptors involved in cell adhesion

Question 21

What is GPIIb/IIIa involved in ?

Answer 21

Platelet aggregation; implicated in thrombosis

Question 22

What are other integrins involved in ?

Answer 22

Cancer, angiogenesis, osteoporosis

Question 23

Many integrin receptors recognise a ?

Answer 23

A RGD sequence (Arg-Gly-Asp)

Question 24

Hence, peptidomimetics, mimics ?

Answer 24

Hence, peptidomimetics, mimicking RGD sequence, have been made