Corticosteroids: History, Creation and Receptors

• Corticosteroids

History and Creation

• Cortisone, the parent drug, was among the first corticosteroids isolated for therapeutic use
• Developed in the 1940s, cortisone marked a new era in treating inflammation and autoimmune diseases
• Edward Calvin Kendall, Tadeus Reichstein, and Philip Hench isolated cortisone from the adrenal cortex in the 1930s-1940s
• The isolation of cortisone earned Kendall, Reichstein, and Hench the Nobel Prize in Physiology or Medicine in 1950
• Clinical use of cortisone to treat rheumatoid arthritis and inflammatory conditions began in 1949
• Cortisone revolutionized medical care, becoming an effective treatment where few existed before
• Synthesizing cortisone was complex, involving cholesterol extraction from animal sources like cow bile

Receptors

• Mineralocorticoid Receptor (MR) targets mineralocorticoids like aldosterone and fludrocortisone
• Glucocorticoid Receptor (GR) targets glucocorticoids such as cortisol, prednisone, and dexamethasone

Pharmacological Effects

• Glucocorticoids primarily regulate inflammation, immune responses, metabolism, and stress responses
• The impact of glucocorticoids deem them essential for treating autoimmune diseases, inflammatory disorders, and allergic reactions
• Mineralocorticoids, like aldosterone, mainly regulate electrolyte balance and fluid homeostasis
• Mineralocorticoid activity affects the kidneys, colon, and sweat glands

Pharmacophore

• The pharmacophore for corticosteroids is based on the steroid nucleus
• The four-ring carbon system is composed of A, B, C, and D rings
• Steroids have 3 six-sided carbon rings and 1 five-sided carbon ring

SAR

• A 11β-hydroxy is required for glucocorticoid activity
• A Δ1,2 increases glucocorticoid activity
• The 3-keto and Δ4,5 are essential for activity in both gluco- and mineralocorticoids
• A 21-OH is required for mineralocorticoid activity but is not always needed for glucocorticoid activity
• A 16-substitution may decrease mineralocorticoid activity
• A 6α- or 9α-halogenation (F) enhances activity in both gluco- and mineralocorticoids

Analogues of Corticosteroids

• Adapting Cortisone to Prednisone involved using bacteria to oxidize cortisone due to its unpleasant side effects
• Prednisone yielded more effective treatments with minimal negative reactions
• Hydrocortisone was adapted to Dexamethasone by adding Fluorine, a double bond at C1-2, and a methyl group at C16
• Dexamethasone is a highly potent corticosteroid, modified for better selectivity
• Dexamethasone has stronger anti-inflammatory properties, but is less prone to causing water and sodium retention
• Hydrocortisone was adapted to Fludrocortisone, adding Fluorine at C9 and a methyl group on C17, while removing the aldehyde group at C18
• Hydrocortisone was modified to enhance its mineralocorticoid activity while maintaining glucocorticoid effects
• Adapting Hydrocortisone to Fluocinolone involved adding Fluorine at C6 and C9
• Fluocinolone was modified to enhance glucocorticoid activity and reduce mineralocorticoid activity, while the fluorine atoms enhance stability and potency
• Adapting Prednisone to Methylprednisolone involved adding a methyl group at the C6 position and an OH group at C11
• Methylprednisolone was designed to be more potent with more favorable side effects versus Prednisone, such as fluid retention and high blood pressure

Prednisone Synthesis

• Prednisone is synthesized through dibromination using molecular bromine, producing a 2,4-dibromo-derivative of dihydrocortisone
• The process involves dehydrobromination with 3,5-lutidine
• The acetyl group is then hydrolyzed using potassium bicarbonate, producing the desired prednisone
• Prednisone can also be synthesized by dehydrogenating cortisone

Prednisone Effects

• The carbonyl group at C-3, with the ketone group at C-11 allows it to bind effectively to the glucocorticoid receptor
• Prednisone is able to suppress pro-inflammatory gene expression due to the two groups at C3 and C11
• Prednisone suppresses the immune system by binding to the glucocorticoid receptor
• Converting the C11 ketone group to an OH group increases both stability and the affinity of the molecule for the glucocorticoid receptor, this enhances glucocorticoid potency
• Prednisone is a strong anti-inflammatory and immunosuppressant
• Prednisone is less likely to cause sodium and water retention, edema, and hypertension

Synthesis Reasons

• Creating new analogues helps to minimize side effects, while improving a drugs potency, and selective activity
• New analogues allows minimization of toxicity and side effects
• New analogues allows consideration of metabolism and bioavailability
• Developing new analogues is important to combat resistance

Uses and Benefits

• Cortisone is mainly used to treat inflammation and autoimmune conditions but has significant mineralocorticoid side effects
• Hydrocortisone, a natural form of cortisol, is used for adrenal insufficiency and inflammatory conditions, with the same effects as cortisone, but with better balance of glucocorticoid/mineralocorticoid effects
• Prednisone is used for more effective anti-inflammatory therapy with fewer side effects, making it more suitable for long-term therapy
• Dexamethasone has strong anti-inflammatory effects
• Dexamethasone is used in severe conditions like shock, and also in cancer treatment to reduce swelling and inflammation