4. Medicinal Chemistry of Corticosteroids Flashcards
1. Understand the terms pharmacophore, lead compound, SAR etc 2. Understand the process and purpose of SAR studies 3. Recognise the general structure of corticosteroids 4. Understand the general SARs of the corticosteroids 5. Structural classes of the corticosteroids - Classification by strength and structure - Be able to classify a corticosteroid if structure is provided 6. You do not need to know the specific structures of corticosteroids
Structure-Activity Relationship (SAR)
Correlation of a molecule’s structure with its biological activity
During a SAR study a number of compounds are made, with slight structural variations to the original (lead molecule) & the biological activity of each one determined
Aim of SAR
- Determine which parts of the lead molecule are essential for biological activity & which parts cause undesired side effects
- Develop a structurally similar compound (analogue) of the lead compound with the best combination of therapeutic properties
Pharmacophores
Contains only the relevant groups that interact with a receptor & are responsible for the activity
How to use SARs to determine the pharmacophores?
Remove single binding group from analogue
If bioactivity is much lower after modification, then that functional group is important for binding to the biological targtet
Corticosteroids
- Steroid hormones that are produced in the adrenal cortex
- Involved in a wide range of physiological processes such as stress and immune response
Corticosteroids - Regulation of:
- Inflammation
- Carbohydrate metabolism
- Protein catabolism
- Concentration of blood electrolytes
- Behaviour
Structure & biosynthesis of corticosteroids
- Synthesised mainly in the adrenal glands
- ABCD ring structure (ABC 6 sided, D 5 sided)
Side effects of corticosteroids (cortisone)
- Anxiety
- Hypertension
- Osteoporosis
- Addiction
Categories of corticosteroids
- Glucocorticoids (GCs) - regulate glucose metabolism
2. Mineralocorticoids - influence salt & water balances
Glucocorticoid - uses (treat conditions)
- Arthritis
- Dermatitis / eczema
- Allergy
- Asthma
- Systemic lupus
- Inflammation of bowel - Crohn’s disease & colitis
Cushing’s syndrome - side effect
- High blood pressure
- Obesity
- Round red face
- Poor muscle tone
Glucocorticoids - mechanism of action (3 steps)
- Corticosteroids bind to GC receptors in the cytoplasm
- GR moves to nucleus & dimerises - dimer binds glucocorticoid response elements (GREs) & coactivator molecules
- Bind leads to activation of genes encoding anti-inflammatory proteins (transactivation) e.g. lipocortin
- Also suppresses transcription of genes encoding pro-inflammatory mediators (transrepression) e.g. COX-2
SAR studies of Cortisone - Structure modifications to improvement anti-inflammatory properties
- -HO at C11
- Double bond at C1 - C2
- -F at C9
- -OH at C16
- -F at C6
See image on notes
SAR studies - Fluorine isosteres
- Fluorine is more electronegative than hydrogen: alter electronegative properties, alter pKa, act as H-bond donor
- C-F bonds are extremely strong - strategic positioning at site of enzymatic oxidation can reduce metabolism of the drug
SAR - possible biological effects
- Binds to receptors / enzymes -> targets - increased/decreased affinity for targets, binds to other targets
- Solubility - water solubility, lipophilicity, permeability, membrane proteins
- Metabolism - CYP450
Many steroids developed empirically - precise knowledge of the function of each chemical change not precisely known
