Ezetimibe and Thyroid Hormones Overview

Ezetimibe

• Approved in 2002
• Reduces LDL, total cholesterol, and triglycerides
• Increases HDL
• Prevents cholesterol absorption from diet
• Useful in hyperlipidemias (type IIa, IIb, III, IV, and V)

Thyroid Hormones

• Crucial for growth and development
• Stimulates metabolism in most tissues (except adult brain)

Thyroid Hormone Function

• Increases mitochondrial oxidative phosphorylation
• Maintains amino acid and electrolyte transport into cells
• Increases calorigenesis and oxygen consumption
• Stimulates protein synthesis (structural & enzymatic)
• Regulates carbohydrate metabolism (accelerates insulin degradation & increases gluconeogenesis)
• Stimulates lipid metabolism (reduces plasma cholesterol)
• Increases cardiovascular and nervous system sensitivity to catecholamines (leading to increased heart rate, cardiac output, and arousal)

Thyroid Hormone Synthesis Requirements

• Requires tyrosine (amino acid) and iodine (trace mineral)
• Begins with thyroglobulin synthesis, which is post-translationally modified in unique biochemical reactions

Thyroid Hormone Biosynthesis Process

• Iodide is oxidized to iodine by thyroperoxidase (TPO) in the presence of hydrogen peroxide (H2O2)
• Iodine binds to the 3' position in the tyrosyl ring, forming 3-monoiodotyrosine (MIT)
• Another iodine binds to the 5' position of MIT, creating 3,5-diiodotyrosine (DIT)
• T4 is formed by the condensation of two DIT molecules
• T3 and reverse T3 (rT3) are formed by the condensation of DIT and MIT
• These biosynthetic processes are controlled by the hypothalamic-pituitary-thyroid axis feedback mechanism

Thyroid Hormone Drugs

• Used as replacement therapy in thyroid gland deficiency
• T3: L-3,3,5-triiodothyronine
• T4: L-3,5,3,5-tetraiodothyronine (thyroxine)

Thyroid Hormone Drug Structure-Activity Relationships

• Contain two aromatic molecules (A & B) linked via a heteroatom (O or S)
• Ring B contains an amino acid side chain with at least three carbons
• Ring A must be perpendicular to ring B with a 120° angle
• Ring B must be substituted at positions 3 and 5 with halogen (lipophilic group) (iodine is most active)
• Ring A must be substituted at position 3 with halogen
• T3 (3 iodines) is less active than T4 (4 iodines)
• Ring A must contain phenolic OH for receptor binding

Levothyroxine Sodium

• Obtained from domesticated animal thyroid glands
• Also prepared synthetically
• Treats decreased thyroid function

Liothyronine Sodium

• Same uses as levothyroxine, including:
  • Hypothyroidism treatment
  • Male infertility
  • Certain gynecological disorders

Anti-Thyroid Drugs

• Used for hyperthyroidism (excess thyroid hormone production)
• Preparation for surgery
• Thiourea and related compounds are toxic
• Useful drugs include 2-thiouracil derivatives and 2-thioimidazole derivatives
• These drugs prevent iodine incorporation into thyroxine and triiodothyronine precursors

α-Glucosidase Inhibitors

• Acarbose inhibits the breakdown of complex saccharides in the intestine by α-glucosidase
• Mimics sugar structure and binds to the enzyme with higher affinity than the natural substrate
• Decreases monosaccharide absorption and postprandial blood glucose peaks
• Useful for postprandial hyperglycemia
• Avoid consuming glucose
• Can cause colonic distress (diarrhea, flatulence, and cramping)

Meglitinides

• Similar mechanism of action to sulfonylureas, but without toxicities

Incretins

• Gastrointestinal hormones that increase insulin release from pancreatic beta cells after eating
• Inhibit glucagon release from alpha cells

Diuretics

• Increase urine formation
• Inhibit sodium reabsorption in the kidney
• Acidosis occurs due to loss of bicarbonate (HCO3-)

Heterocyclic Sulfonamides

• Examples include acetazolamide (Diamox) and methazolamide (Neptazane)

Diuretic Structure-Activity Relationships

• Acetazolamide is the prototype
• Higher lipid/water partition coefficient and lower pKa lead to greater carbonic anhydrase inhibition and diuretic activity
• Sulfamoyl group is essential for activity
• Sulfamoyl nitrogen must remain unsubstituted
• Methyl substitution on one of the ring nitrogens increases potency
• Sulfamoyl group must be attached to an aromatic moiety

Ethacrynic Acid Synthesis

• Involves a series of reactions including Friedel-Crafts acylation and amination with methylamine

Site 3 Diuretics: Thiazide and Thiazide-like Diuretics

• Include chlorothiazide, hydrochlorothiazide (HCTZ), benzthiazide, cyclothiazide, indapamide, chlorthalidone, bendroflumethizide, metolazone, etc.

Thiazide Structure-Activity Relationships

• Position 2 tolerates small alkyl groups (e.g., CH3)
• Position 3 is critical for potency and duration of action