Chemistry of Steroids 2

Dr. Beck (Dr. Carvalho)

11-beta-HSD 1

found in the liver

converts cortisone (inactive) → cortisol (active)

11-beta-HSD 2

found in the kidney

converts cortisol (active) → cortisone (inactive)

Cholesterol structure

17-alpha-hydroxypregnenolone structure

17-alpha-hydroxyprogesterone structure 

11-deoxycortisol structure

hydrocortisone (cortisol) structure

cortisone structure

pregnenolone structure

progesterone structure

21-hydroxyprogesterone (11-DOC) structure

corticosterone structure

aldosterone structure 

pregnane ring system

Fluorometholone structure

Alclometasone dipropionate structure

Fludrocortisone structure

6-methylprednisolone structure

mineralocorticoid receptors (MR)

regulate water retention and salt balances through agonist functional

Aldosterone: receptor activity

most potent endogenous mineralocorticoid agent

weak affinity for glucocorticoid receptors

Aldosterone: hemiacetal form

aldehyde → hemiacetal

due to this reaction: escapes inactivation in the kidney, poor ligand for GR 

necessary for adrenocorticoid activity (SAR)

all the above

Fluorometholone: SAR

exception (nothing at C21 position)

Fluorometholone: drug properties    

ophthalmic suspension/ointment

11-beta-OH group

necessary for glucocorticoid activity

addition of a double bond from C1 → C2

increases glucocorticoid activity selectively

C1 → C2 double bond: structural changes

boat conformation, slows metabolism, increases DOA

6-alpha substitutions (alkyl group/halogen)

increase glucocorticoid activity

substituents at the 7-position

decrease anti-inflammatory activity

Alclometasone dipropionate: drug properties

Aclovate, topical cream/ointment, low potency

Fluorine at C9

increases MR and GR activity but to different degrees

fludrocortisone: drug properties

Mineralocorticoid replacement in adrenal insufficiency, oral tablet (generic only, 21-acetate) 

fludrocortisone: potency

10x activity of cortisol on GR

125x activity of cortisol on MR

C16 methyl/hydroxyl substituents

eliminates mineralocorticoid activity

Triamcinolone, betamethasone, dexamethasone: drug properties

no mineralocorticoid activity