STRUCTURE ACTIVITY

RELATIONSHIP OF STEROIDS
By Dr. Preetish Ku. Panigrahy

As we go along

Introduction to SAR

SAR of Corticosteroids

SAR of Sex hormones

The structureactivity relationship (SAR) is the

relationship between the chemical or 3D structure of
a molecule and its biological activity.
The analysis of SAR enables the determination of
the chemical groups responsible for evoking a target
biological effect in the organism

Structureactivity

relationships

are

usually

determined by making minor changes to the

structure of a lead to produce analogues

Those changes are..

Size and shape of the carbon skeleton

Nature and degree of substitution and

Stereochemistry of the lead molecule

SAR OF STEROIDS

Why SAR of Corticosteroids?

Chemical

modifications leads to generation of

derivatives with:1.

Greater separation of glucocorticoid &

mineralocorticoid activity

2.

Different potency & duration of action

Cyclopentano perhydro phenanthrene

nucleus

Glucocorticoid activity requires 11 hydroxyl(OH) group , an -hydroxyl group linked to

C17

Increases GC activity,
Enhanced GC/MC potency ratio.
Metabolized more slowly than hydrocortisone
Salt retaining activity decreases
Anti-inflammatory effect enhances

6 substitution on Ring B

6-Fluorination

6-fluoro has less salt retention properties than 9fluoro.

Fluocinolone

Fluorination at 9 alpha
Enhances both GC and MC
activity

Fludrocortisone (9-fluorocortisol)
enhanced activity at the GR (10 times relative to
cortisol)
greater activity at the MR (125 times relative to
cortisol).

1,2 double bond in ring

A + other substitutions
at C16 on ring D

the 9-fluoro
derivatives

C 16

Anti-inflammatory effect
enhances and saltretaining effects weakensC16 & C17
further.

Acetonide b/w OH groups at

Substitution at C16 on ring D

More GC activity & anti inflammatory

activity
Eliminates MC activity

9chlorination

9-chloro derivative of betamethasone

Beclomethasone

dipropionate

Increase stabilization
Increase lipophilicity
Increase bronchial tissue absorption
Increase duration of action

Lipophilicity & topical/systemic

potency ratio

Acetonide b/w OH groups at C16 & C17

Esterification of OH groups with Valerate at C17

Esterification of OH groups with propionate at

C17 & C21

Substitution of OH group at C21 with Chlorine

17 hydroxyl group on ring Desterification of the hydroxyl group

Valerate at C17
Propionate at C17 and
C21
Substitution group at
C21 with chlorine

Mineralocorticoid activity
requires
Hydroxyl

group at C21 on

ring D
Aldehyde group at C18

Estrogen, Progesterone, Androgen

Testosterone,

21carbon3keto D4

lacks the 2-carbon side-chain attached

to the 17 position, making it a 19carbon
steroid .

18carbon

Ethinyl substitutions at the C17

position greatly increase oral
potency by inhibiting first-pass
hepatic metabolism.

Alkylation of the
aromatic ring decrease
the activity.

Points to remember
Aromatic ring with C-3-OH is essential for activity.
Alkylation of the aromatic ring decrease the activity.
The 17b-hydroxyl is essential for activity.
Unsaturation of ring B decreases the activity.
17alpha- and 16 position when modified enhance the
activity.

PROGESTINS

Compounds with biological activities similar to those of

progesterone

17-Hydroxyprogesterone /Hydroxyprogesterone
caproate

Used parenterally due to first-pass hepatic metabolism.

Substitutions at the 6-position of the B ring yield orally

active Medroxyprogesterone acetate

Selective progestational activity.

Contd..

Steroidal nucleus essential for activity.

Have some androgenic activity.
Removal of the 19 CH3 increase activity.
Unsaturation of ring B or C increase the activity.
Removal of the keto function remove androgenic activity

Therapeutic Androgen preparations

Esterifying a fatty acid to
the 17 hydroxyl group
compound that is even
more lipophilic

LYMPHATIC
SYSTEM

They are less

androgenic than
testosterone itself,
they cause
hepatotoxicity

Retarded its hepatic

catabolism

Changes that increase GC activity

Additional double bond b/w 1 & 2 carbon

atoms

Alpha methylation at 6th position

Alpha fluorination at 9th position

Substitution at 16th position

In a
nutshell

SUMMARY.