WEEK 3 Flashcards
What is a Prodrug ?
Inactive compound converted to an active drug in the body
What is an example of a Prodrug and its use ?
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.
What can act as a prodrug to nordazepam ?
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
Is Aspirin a prodrug ? explain what is hydrolysed ?
- Aspirin is a prodrug; the ester is hydrolysed in the stomach to a phenol derivative.
- The latter, when used, gives rise to gastric bleeding.
What happens to the action of Fluphenazine ?
- 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
What can subtle difference in size/shape/conformation of the drug affect ?
Drugs can bind to biological receptors or enzymes; subtle differences in size/shape/conformation of the drug can affect binding.
How do “floppy molecules” bind and why ?
“Floppy” molecules have many degrees of freedom and bind less tightly to receptor or enzyme
High energy “active” conformation may ?
Be stabilised with conformational restriction. Drug can “lock” onto receptor or enzyme
What can add conformation restriction ?
Further ring adds conformational restriction
What is Metoclopramide ?
- A dopamine receptor (D2) antagonist with anti-emetic and prokinetic properties (5HT3 antagonist).
- Cocaine has 5HT effects.
What is increased 5HT3 antagonism used for ?
Used to treat nausea during chemotherapy.
What is Bioisosteres ?
Exchange of an atom or group with a similar atom/group with similar biological properties
A lead compound may have good affinity but ?
Have problems in terms
of bioavailability, toxicity or metabolism
So bioisosterism is used to?
Improve lead quality- lead optimisation
What is Fluorine a classic replacement for ?
Fluorine is a classical replacement for H (isostere); similar size but blocks P450 metabolism
When should you prevent using fluorine in medicinal chemistry ?
Prevent in vivo racemisation
What are some functions of Fluorine in Medicinal chemistry?
- 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
Explain what happens when you replace OCH2 in Propranolol ?
- Replacing OCH22 with CH=CH, SCH, CH2CH2 eliminates activity
- Replacing OCH2 with NHCH2 retains activity
- Implies O involved in binding (HBA)
Explain the Dermorphin Analogues ?
- 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
What are Integrins ?
Surface receptors involved in cell adhesion
What is GPIIb/IIIa involved in ?
Platelet aggregation; implicated in thrombosis
What are other integrins involved in ?
Cancer, angiogenesis, osteoporosis
Many integrin receptors recognise a ?
A RGD sequence (Arg-Gly-Asp)
Hence, peptidomimetics, mimics ?
Hence, peptidomimetics, mimicking RGD sequence, have been made
