Thyroid function and Thyroid Drugs

. . (1.5 h)

 Thyroid Function and Thyroid

Drugs

1. thyroid hormones 2. hormones 3. hormones 4. Anti-thyroid thyroid thyroid hormones thyroid

Contents
Thyroid hormones Thyroid hormones metabolism hypothyroid hyperthyroid Thyroid hormone analogs Thyroid receptor

1. Foye, W.O., Lemke, T.L. and Williams, D.A. 2001. Principal of medicinal chemistry, 5th Ed. Philadelphia: Williams and Wilkins, Philadelphia. 2. Webster, L.T., 1996. Goodman and Gilman s The Pharmacological basis of therapeutics, Pergamon Press, 9th Edition, New York.

Thyroid hormones: Iodinated amino acid

Liothyronine (T3) Levothyroxine (T4) Other structurally similar compounds -reverse T3 and 3,3'-diodothyronine (T2)
T3 or 3,5,3 -triiodoL-thyronine

T4 (Thyroxine)

or 3,5,3 ,5 tetraiodo-Lthyronine

-inactive metaboli tes of Reverse T3 (rT3) or Reverse T3 triiodothyronine and T4.

T2 3,3'-

diodothyronine

Thyroid hormones
aromatic rings linked by an ether. Differences in the number and position of the iodine atoms. extremely important for activity and determine Ether bridge the structure-activity relationships
HO
4' 5' 6' 6

Thyroid hormones: L-alanine side chain, two

I
4 1'

COOH NH 2

F
3'

E
2 3

O I

2'

Outer ring

Inner ring

Alanine side chain

Synthesis of Thyroid hormones

Thyroid gland : Thyroglobulin They are synthesized in the body by coupling reactions of monoiodotyrosine (MIT) and diiodotyrosine (DIT).
Alanine (aminopropionic acid)
5 4 6 3 1 2

COOH NH2

I HO I

COOH NH2

HO I

Iodine substituted tyrosine

DIT or

MIT or

Monoiodotyrosine

Diiodotyro sine

I HO I

COOH NH2

COOH NH2 I

HO

DIT

DIT

I HO I I O I COOH NH2

T4

5 4

6 3 1 2

COOH NH2

COOH NH2 I

HO I

HO

MIT

DIT

HO I

I O I

COOH NH2

T3

I HO I I O I COOH NH2

T4

5 4

6 3 1 2

COOH NH2

COOH NH2 I

HO I

HO

MIT
I HO

DIT

COOH NH2

rT3

O I

I HO I I O I COOH NH2

T4

T3 is more active than T4. T2 and rT3 are inactive. T4 has a longer duration of action than T3

The number and position of the iodine atoms

Thyroxine (T4)
T4 : Major thyroid prohormone T4 T3 T3 Activation

T4

rT3 T1/2 (T4) > T1/2 (T3) Blood : T4 > T3 Tissue, external gland: T3 > T4 Activity: T4: liver, kidney T3 : muscle, brain

Inactivation

Formation of thyroid hormones

Active uptake of iodide by follicular cells Oxidation of iodide : Iodotyrosines are formed. Coupling of iodotyrosine residues Proteolysis of thyroglobulin and releasing of iodothyronines Conversion of thyroxine to triiodothyronine Transport of thyroid hormones in blood

Schematic representation of thyroid hormone biosynthesis and secretion

HO HO Thyroglobulin synthesis O O I IIOxidation Tyrosine IDeiodination HO
I I

I-

HO I
I

HO

TPO

Incorporation
I

O
I

MIT DIT

Coupling DIT MIT T3 HO Reasorption

I I I

O
I

Secretion T3 T4

T4

Follicle cell

Follicular lumen

Metabolism of thyroid hormone

Cn gt n o ju aio
HO

D io in t n e d aio
I I O I

D ca o y tio e rb x la n
COOH NH2

in e rin nr g

o t rrin ue g
I

O id t ed a in t n x aiv e m aio eh rb n cle a e t e o d vg

Thyroid diseases
Hypothyroidism Hyperthyroidism

Thyroid diseases & Therapeutic agents

Myxedema

Hypothyroidism

Simple goiter Cretinism

Give thyroid hormone preparation

-Desiccated thyroid -Partially purified thyroglobulin -Synthetic, crystalline T4

Thyroid diseases & Therapeutic agents

Hyperthyroidism
Give anti-thyroid drugs
-Thyroid peroxidase inhibitor (TPO inhibitor) TPO: Iodination, coupling in biosynthesis of thyroid hormone -Thyroid hormone analogs :Activity at receptor SAR of thyroid hormones

Thyroid peroxidase inhibitor (TPO inhibitor) -Thioamide /Thiourelene family: Sulfated uracil or
imidazole

I
HN S

Antithyroid compounds: No effect to

thyroidal thyroglobulin and the hormone outside gland PTU>MTU II 10 times

Thioam Thiouracil ide

N H

HN

CH3
Tasteless

R=H Methylthiouracil R = CH3 Propylthiouracil R = n-C3H7 (PTU):TPO inhibitor

block T4 to T3

Methimazole (MMI) O
CH3CH2O C N N S CH3

Carbimazole

Structure of thioamide and thiocarbamide

Thioureylene : forms

Thioketo

or

thioenol tautomeric

N S N HS

N N

Thioketo

Thioenol

Structure Activity Relationships of Thyroid Hormones: The Role of the Iodine Atoms

SARs of Thyroid hormones

5' 4' 6' 4

HO

6 5 1

COOH NH2

3'

2'

1'

O
3

Aliphatic side chain Alanine bearing ring Bridging atom Phenolic ring Phenolic hydroxyl group Conformational properties of thyroid hormones

Relative rat antigoiter activity of thyroxine derivatives (Alanine side chain)

R5' HO R5 R1

F
R3'

E
R3

Aliphatic side chain

5' 6

HO
4'

I
6' 4

1
*

COOH NH2

3'

2'

1'

O
3

Alanine side chain should be at C-1 of inner ring Activity of L-isomer > D-isomer Carboxylate is more important than zwitterionic alanine side chain

Aliphatic side chain (Cont.)

5' 6

HO
4'

I
6' 4

1
*

COOH NH2

3'

2'

1'

O
3

Number of atom linked with carboxylate side chain is necessary : Acetic acid side chain or carbon 2 atoms Activity is reduced with formic acid or carbon chain longer than propionic acid Activity of ethylamine analogs < carboxylic acid analogs

THE IMPORTANCE OF THE 3- AND R' 5-IODO GROUPS

5

HO

R5 O R3

R1

R3'

Bridging atom

Alanine bearing ring (Inner ring)

I

HO
4'

5' 6'

I
4

6 5 1

COOH NH2

3'

2'

1'

O
3

inner ring should have iodine atom at C-3 and C-5. Removing of iodine from inner ring at C-5: inactive (due to losing diphenyl ether conformation). ------- rT3, T2 Replacement of 5-I or 3-I by bromine atom, methyl : still active. Replacement of 5-I or 3-I by alkyl group is larger than methyl group ex. isopropyl and secondary butyl: inactive.

Bulkiness of the Iodine and Conformation Nature of the Rings Features:

to restrict rotation and "lock in" the active, perpendicular conformation the ability of the compound to bind to its receptor. The 3- and 5-iodo groups are extremely large and bulky and when placed at HO positions 3 and 5 of the ring, force the F two aromatic rings to remain I perpendicular. O
COO I H NH3

SUBSTITUTIONS OF THE 3- AND 5-IODO GROUPS

Replacement of 3,5-iodine atoms by other large bulky groups will result in the retention of activity, while replacement of these atoms by smaller groups will HO decrease activity.
I O COO I H NH3

Thus, the size of the substituents at positions 3 and 5 increase, the ability of

Bridging atom
S, O, CH2 :Active Ether bridge
5'

(biphenyl: inactive, conformation change)

6

HO
4'

I
6' 4

COOH NH 2

3'

2'

1'

O
3

Outer ring

Inner ring

Alanine side chain

THE IMPORTANCE OF THE 3' AND 5'IODO GROUPS R'

5

R4' R3'

R5 O R3

R1

Phenolic ring
3 or 5-I on Phenolic ring affect to activity and affinity of thyroid hormone
5'
I

HO

4'

3'

n-propyl or isopropyl

3, 5 substituent = non-polar e.g. halogen or alkyl group : Increase F< Cl <Br <I activity

CH3< CH2CH3 < CH(CH3) 2 (effect of size of substituent)

Activity of 3-halogen > 3 and 5-halogen as phenolic hydroxyl gr. is ionised better and bind to TBG higher, hence less bind to receptor.

Phenolic hydroxyl group

I

5'

HO

4'

3'

4-Phenolic hydroxyl : Ionizable 4-amino: less active

H-bonding

No 4-substitued: active (change to 4-OH in body) 4-CH3 : inactive , but 4-OCH3 is active because it can be changed as 4-OH.

pKa of T3 &T4
Acidity: T4 >T3 At pH 7.4 : ionization of T4 > T3 bind to plasma protein is better. Thus, T1/2 (T4) > T1/2 (T3)
TBPA= Thyroid binding prealbumin
I

HO

HO

T4
I

T3

pKa = 6.7

pKa = 8.5

Conformational properties of thyroid hormones

HO

5 proximal group
H I O COO I H NH3

3 distal group
(i.e., farthest away)

2 blocked group
HO

Compound B&C = distal analogs

HO

CH3

H3C
HO H3C H3C

OR

A
HO

OR

B D

C
OR
I H2 N COOH

H3C

OR

R=

B>C>D>A

Structure of distal and proximal compounds

Side-chain conformations of thyroid hormone

HO

I O COO I HO H NH3

Transoid-

I O I

NH3 COO

Cisoid-

The outline of thyroid receptor

HO I I O I H

COO NH3

The Binding of T3
Unlike T4, however, the lack of a 5'-Iodo group allows T3 to perfectly fit into the receptor. The steric hindrance present in T4 is not seen with T3; therefore, T3 is more active (i.e., more potent) than T4.

The Binding of T4
Note that a similar hydrophobic cavity for the 5'-iodo group does not exist. Hence, steric hindrance will decrease the binding of T4 to the thyroid receptor.