LEC5 - Corticosteroids

Question 1

Describe an SAR

Answer 1

Structural-Activity Relationship.

The correlation of a molecule’s structure with it biological activity

Question 2

Describe how SAR studies are conducted

Answer 2

Development of a number of compounds with slight structural variations to the original, and the biological activity of each one determined

Question 3

Define lead molecules and analogues

Answer 3

Lead molecules - the original molecule

Analogues - compounds structurally similar to the lead compound

Question 4

Define pharmacophores

Answer 4

Molecules which contain only the relevant groups that interact with a receptor and are responsible for activity.

Question 5

Describe the process of determining pharmacophores through SARs

Answer 5

1. ) Identification of a lead structure
2. ) Identification of possible drug target binding groups
3. ) Synthesis of a series of analogues where one binding group is removed
4. ) Test all analogues for biological activity
5. ) Identification of pharmacophore

Question 6

Explain where steroid hormones are produced and briefly describe their functions

Answer 6

Produced in the adrenal cortex.

Functions: regulation of…

• Inflammation
• Carbohydrate metabolism
• Protein catabolism
• Behaviour

Question 7

Provide 2 examples of corticosteroids are briefly describe their function

Answer 7

Glucocorticoids - regulate glucose metabolism

Mineralocorticoids - regulate salt and water balance

Question 8

Explain the mechanisms of action of corticosteroids

Answer 8

• Coritcosteroids bind to glucocorticoid receptors in the cytoplasm
• GR moves to nucleus and demises
• Dimer binds to glucocoritcoid response elements (GREs) and coactivator molecules

Question 9

Explain how corticosteroids affect inflammation

Answer 9

Corticosteroids lead to activation of genes encoding for anti-inflammatory proteins and suppression of transcription of genes encoding for pro-inflammatory mediators.

Anti-inflammatory: lipocortin
Pro-inflammatory: COX-2, iNOS

Question 10

Discuss why fluorine is an effective isostere to hydrogen

Answer 10

Fluorine and hydrogen have a similar size which means there is little change in steric effects on the binding receptor.

However, fluorine is more electronegative than hydrogen which means it can alter the pKa of certain functional groups and act as an H-bond acceptor.

Additionally, fluorine forms a strong bond with carbon which means it can be strategically positioned to prevent oxidation and reduce metabolism of the drug.

Question 11

Describe when it would be appropriate to use less potent topical steroids

Answer 11

When dealing with thin skinned or sensitive areas.

Example: armpits, eyelids, diaper area

Question 12

Describe when it would be appropriate to use moderately potent topical steroids

Answer 12

Skin conditions such as:

• Eczema
• Scabies

Question 13

Describe when it would be appropriate to use highly potent topical steroids

Answer 13

• Psoriasis
• Discoid lupus
• Poison ivy exposure