Endocrines

Steroids
Basal secretion
- Glucocorticoids
- Mineralocorticoids
- Sex hormones

Glucocorticoids
cortisol ( Receptor H-bond )
Glucocorticoid receptor

- Carbonyl gr. C-3 Arg-611 Gln570 ( Arg)
- O-atom C-11 H-donor
- 17-ketone side chain ( -OH H-donor =O
H-acceptor)
- 17 -OH affinity

C3 keto group
17-ketone side chain

hydrocortisone

DB at C 4-5
C17-OH
C11-OH

Structural modification
- C11-OH, C17-OH glucocorticoid
- 17 hydroxyl glucocorticoid
mineral
- Double bond 1,2 antiinflammatory activity Rc
( chair formhalf chair form C3-carbonyl
Rc)
- methyl C6 anti-inflammatory activity
- methyl hydroxyl C16

- F C 9 (EN ) inductive effect

e-H ( OH) partial positive
H-bond Metabolism
11-OH ( oxidized ketone )
** Hydrocortisone High
glucocorticoid low mineralocorticoid
3, 11, 17
- BD 1-2 carbon

Prednisolone

- BD 1-2 carbon
- F C 9
- 16-OH
Triamcinolone
- Triamcinolone acetonide prodrug
hydrolyze 16,17-OH=triamcinolone
active drug (m
ineralocorticoids)

- Acetonide

lipophilicity

Clobestasol
C21-Cl potency
C16-methyl & C9-F
lipophilic topical
Clobestasol
Point

- DB at C 4-5 C3 ketone
- C6,C16-methyl C9-F

Methylprednisolone 6 methyl

activity
- Triamcinolone 9-F OH 16
activity
- Dexamethasone Betamethasone F
16 methyl activity

** 16 Methyl
receptor dexamethasone
methyl 16
side chain 17
receptor betamethasone methyl
side chain 17

Dexamethasone Clearance
betamethasone potency 2

Sex hormones
1.Estrogen steroids
Steroid structure
(planar)
ring A (Ring A planar
estrogen-specific receptor
- interaction)

- 17 -OH
- 3-OH
- Aromatic ring A

Metabolism: Oxidation & racemization Phase

I conjugate with glutathione phase II

Modification: ethinyl group 17

ethinyl estradiol (EE)
Mestranol: prodrug EE
demethylation methoxy 3
active form

Nonsteroidal estrogens
Stilbene derivative
Trans - Diethylstilbestrol
(DES)
trans
cis
S/E :

Point

- hydroxyl 3 aromatic ring

-
- Alkylation aromatic ring
- 17b-hydroxyl 3-OH

- ring B
- 17- 16 lipophilicity
2. Progestins

3 ketone
4-5 double bond
17B-ketone
** Glucocorticoid
11-OH 17 OH
glucocorticoid

 R group OH
17 progesterone
Metabolism: reduction C3, C4, C20
Progesterone (21 carbons): low absorption & rapid
first pass metabolism
Structural modification
- acetoxyprogesterone: acetyl
17- duration
- Medroxyprogesterone acetate:
carbonyl 6 acetate 17-
selectivity progesterone activity

Medroxyprogesterone acetate

methyl 13 ethyl potency

ketone c 16 androgenic effect
norgestimate, desogestrel, gestodene,
nomegestrol, nestorone, trimegestone

norgestrel

norgestimate

Point

- Steroid nucleus
- androgenic effect
- c 19
- ketone c 16 androgenic effect
3. Androgens (C19 carbons)
Anabolic androgenic steroids
Testosterone

C3 carbonyl
testosterone

C17 -OH
Double bone C4-5

- Ring A chair form space

androgen-specific receptor
Progesterone
- 17-OH estradiol estrogen
receptor

- 3 receptor
Structural modification
17 -CH3 orally active anabolic
activity
17-OH androgenic effect

17-ester duration (longer-acting)

C3 ketone 3-hydroxyl androgenic activity
(17-ethinyl )
Anabolic agent
Methyl testosterone

Oxandrone: 17-methyl

Nandrolone: methyl
IM parenteral

Point

- progestin 17B OH
ketone

THYROMIMETIC AND ANTITHYROID AGENTS

T3 : 3,5,3-triiodo-Ltyronine(DIT+MIT)

T4 : 3,5,3,5tetraiodo-Ltyronine(DIT+DIT)

** Active form

T3 & pKa

**
T4

33% T4

**Lipophilicity

5deiodinase

albumin

40% rT3

Metabolism: sulfate
conjugate
Excretion: Urine
BA 95%

T1/2
Glucuronide conjugate
Excreation: 50% urine &
50% feces
BA 50-80%

**
- Aliphatic side chain : L-isomers
D-isomer:
carboxylate series & ethylamine
- Alanine bearing ring : **
I Br
Halogen
- Bridging atom: S, O, methyl
- Phenolic ring : unsubstitute
non-polar : halogen, ethyl gr. (gr.)
- Phenolic hydroxyl group : ionized
- Iodine 3 5

Antithyroid Agent
thioamides

MOA: thyroperoxidase enzyme inhibitor ( Enzyme

)
## tautomers (H atom
thioketo thioenol

## NH 1 gr, C2 thioketo/thioenol
- PTU 5Deiodenase
Methimazole
5 membered ring
-
t1/2 > PTU

Propylthiouracil (PTU)
6 membered ring
** propyl group

prodrug
carbimazole
methimazole

Thyroid replacement therapy


thyroid hormone
Levothyroxine: sodium salt T4 form on
set long duration

** levothyroxine dextrothyroxine
Liothyroninesodum: crystalline T3 (rapid onset and
short duration)

Liotrix: mix T4 and T3 (4:1)

HYPOGLYCEMIC AGENTS
Sulfonylureas

pKa=5.0 sulfone electron

withdrawing gr.

- Sulfonylurea receptor (SUR) type 1

- SUR2 side
effect

- SUR 3 domain TMD0, TMD1, TMD2

SUR1 TMD2

- R TMD0 affinity
- R2 TMD2 selectivity
- R R2 lipophilic

* TMD0 TMD1 TMD2

TMD3

Generation
-

R
TDM0 affinity

R2 C~3-6 atom

lipophilic protein
binding duration

- Chlopropamide
Cl
metabolism

Generation 2 3
- R TMD0 affinity

generation 1
- R2

- Gen2 carboxamide ()
CYP450 Gen3 Gen3 duration

- Lipophilic protein binding

Biguanides: Metformin (MOA: inh. gluconeogenesis)
Isoamylene

Thiazolidinediones: (MOA: agonist PPAR-)

Pioglitazone