Medicinal Chemistry of Thyroid

Thyroid gland description

The thyroid gland, shield-shaped, is a highly vascular, flat structure located at the upper portion of the trachea, just below the larynx.

Thyroid gland function

The thyroid gland has the capability to incorporate iodine into organic substances.

Thyroid hormone origin

Thyroid hormones are iodinated amino acids derived from l-tyrosine.

Types of thyroid hormones

The two types of iodinated hormones are triiodothyronine (T3) and thyroxine (T4).

Function of T3 and T4

T3 and T4 play important roles in regulating metabolism, growth, and development and in maintaining homeostasis.

Metabolic function of thyroid hormones

T3 and T4 control essential functions related to oxygen consumption such as energy metabolism and protein synthesis.

DIT and MIT

The thyroid gland contains two important iodinated amino acids, 3,5-diiodo-l-tyrosine (DIT) and 3-iodo-l-tyrosine (MIT).

Formation of T3 and T4

The coupling of DIT with DIT forms T4, and DIT with MIT forms T3.

Reverse T3

In addition, the thyroid gland contains inactive iodothyronines such as reverse T3 (rT3).

Role of iodine

Iodine is an indispensable component of thyroid hormones.

Iodine absorption

Ingested iodine is absorbed through the small intestine and transported in plasma to the thyroid.

Iodine function in thyroid

In the thyroid, iodine is concentrated, oxidized, and incorporated into thyroglobulin to form MIT and DIT and later T3 and T4.

TSH role

Thyroid hormone synthesis is regulated by TSH, which stimulates thyroglobulin, thyroid peroxidase, and hydrogen peroxide.

Step 1 synthesis

Active uptake of iodide into follicular cells.

Step 2 synthesis

Oxidation of iodide to hypoiodite by TPO and H2O2.

Step 3 synthesis

Formation of MIT and DIT through iodination.

Step 4 synthesis

Coupling of iodotyrosines to form T3 and T4.

Step 5 synthesis

Proteolysis of thyroglobulin and release of T3 and T4 into blood.

Step 6 synthesis

Conversion of T4 to T3 by 5’-deiodinase.

T4 metabolism

T4 is a prohormone and undergoes peripheral metabolism.

Outer ring deiodination

Outer ring deiodination produces T3 (active hormone).

Inner ring deiodination

Inner ring deiodination produces reverse T3 (inactive).

Liver metabolism

T4 metabolism in the liver includes conjugation and oxidative deamination.

Thyroid replacement therapy

Hormone replacement therapy is used in the treatment of hypothyroidism.

Levothyroxine description

Levothyroxine is the sodium salt of T4.

Liothyronine description

Liothyronine is the sodium salt of T3.

Liotrix composition

Liotrix consists of levothyroxine and liothyronine in a 4:1 ratio.

SAR core

The phenyl-X-phenyl nucleus is essential for thyroid hormonal activity.

Side chain SAR

The hormones are derived from L-tyrosine and the L-isomers are more active.

Inner ring SAR

The inner ring is substituted with iodine at positions 3 and 5.

Removal of iodine

Removal of iodine from the inner ring produces inactive analogs.

Phenolic OH SAR

The phenolic hydroxyl group at the 4′ position is essential for activity.

X group SAR

The X group is oxygen and is important for activity.

Outer ring SAR

The outer ring substitutions affect biologic activity and receptor binding.

Antithyroid drugs examples

Methimazole, PTU, and carbimazole are thioureylene derivatives.

Antithyroid drug mechanism

These drugs inhibit thyroid peroxidase and block iodination and coupling reactions.

Thiouracil SAR

The C-2 thioketo/thioenol group and unsubstituted N-1 are essential for activity.

Activity enhancement

The OH group at C-4 and alkyl group at C-6 increase activity.

PTU potency

Maximum activity occurs with a propyl group at C-6 as in PTU.

Methimazole properties

Methimazole has greater TPO inhibitory activity and longer duration than PTU.

Carbimazole

Carbimazole is a prodrug of methimazole.

Mechanism of thioureylene

Thioureylene drugs act as competitive inhibitors of iodination and coupling reactions.