Thyromimetic and Antithyroid Drugs PDF

Thyromimetic and Antithyroid Drugs Paiboon Nuntanakorn, Ph.D. 1 Department of Industrial Pharmacy Faculty of Pharmacy, Silpakorn University 2 Objectives: Comparison between T4 & T3 in term of chemical structure, physicochemical properties, PKs. Ex...

Thyromimetic and Antithyroid Drugs Paiboon Nuntanakorn, Ph.D. 1 Department of Industrial Pharmacy Faculty of Pharmacy, Silpakorn University 2 Objectives: Comparison between T4 & T3 in term of chemical structure, physicochemical properties, PKs. Explain SARs & conformation properties of thyroid hormones & analogs. Explain physicochemical properties, SARs, mechanism of action, use, toxicity of antithyroid drugs. 3 Reference: Lemke, T.L.; Williams, D.A. FOYE’S Principle of Medicinal Chemistry, 7th ed., Lippincott Williams & Wilkins, Philadelphia, 2013, pp.943-963. Evaluation: Midterm#1 Examination 4 Outline Introduction: thyroid hormones (chemical structure, biosynthesis, transport & metabolism) Therapeutic Agents 1. Thyroid Replacement Therapy (natural/ synthetic) :SARs, conformation of thyroid analogs 2. Antithyroid Drugs (Thioamides) Summary 5 Thyromimetic & Antithyroid Agents Thyromimetic Agents (Thyroid Replacement Therapy) : Hypothyroidism Antithyroid Agents : Hyperthyroidism 6 Thyroid Hormones Thyroid hormones are iodinated amino acids derived from L-tyrosine, synthesized in the thyroid gland and stored as amino acid residues of thyroglobulin. glycoprotein as L-tyrosine  7 Thyroid gland Thyroid gland consists of the functional units, the follicles. The center of the follicles is filled with a gelatinous colloids, the main component of which is glycoprotein called thyroglobulin. I follicle ↓ follicular cell https://www.toppr.com/ask/question/give-the-exact-location-of-the-thyroid-gland/ https://www.slideshare.net/slideshow/endocrineht-pitthyr/244684863  T & Tz , difference is I on cuter wing - 8 Thyroid Hormones L-tyrosize jaint - 74 & T , come from 2 together with 2 cromatic 4 iodines band with oxygen rings. ~ oxygen Thyroxine (T4 )(3,5,3,5-tetraiodo-L-thyronine) inner1 ring alanine His OH I group 5' 6 HO 4' 6' I 5 C OOH 3' 1' 2 NH 2 I 2' O 4 3 outer as prie I L-tyrosine Triiodothyronine (T3 )(3,5,3-triiodo-L-thyronine) 5' 6 HO 4' 6' I 5 1 C OOH 3' 1' 2 NH 2 I 2' O 4 3 I I outer ring only found , I indire 9 Iodinated Compounds of the Thyroid Gland Beside T3 and T4, thyroid gland also contains two quantitatively important iodinated amino acids; diiodo-L-tyrosine (DIT) and monoiodo-L-tyrosine (MIT), and a small amounts of 3,3,5-triiodo-L-thyronine (reverse T3, rT3), and 3,3-diiodo-L-thyronine (T2). None of these possess any significant hormonal activity. assian in lodination in one enemnerosigigan ·n I esde Dankeisbienens Iodinated Compounds of the Thyroid Gland in order to make sodium salt from , we put NaOH into it NaOH will. reacts wh cool gray due to the strongest acid group in the structure) T4 = DIT + DIT, T3 IT= DIT + MIT ( net loss of alanine) 10 both T3 T will lost I , relecule of Ala  Biosynthesis of Thyroid Hormones 11 2 111 TPO 2 3 3TPO H2O2 1t 4 10 times TPO = Thyroperoxidase enzyme 12 Biosynthesis of Thyroid Hormones 1.Active uptake of iodide by follicular cells 2.Oxidation of iodide and formation of iodothyrosines: to generate reactive I- species (hypoiodate, OI- ) 3.Coupling of iodotyrosine residues: 2 DIT or DIT+MIT (each with the net loss of alanine) 4.Proteolysis of thyroglobulin and release of iodothyronines 5.Conversion of thyroxine to triiodothyronine; - in the peripheral tissue, about 33% of T4 T3 and 40% of T4 rT3) - about 80% of T3 is derived from circulating T4 13 Transport & Metabolism Both hormones are transported in the blood bound mainly to thyroxine-binding globulins (TBG). When bound, both are not physiologically active but provide a storage pool. for from 13174 important removing enz I Deiodination (by the deiodinase enzyme) is the most ~ important metabolic pathway of the hormone. T4 is a prohormone, and its peripheral metabolism occurs in two ways; has effect ~ -outer ring deiodination by the 5-D, which yields T3 -inner ring deiodination by the 5-D, which yields rT3 L no effect 14 Transport & Metabolism functional structure T4 5-D 5-D rT3 T3 5-D 5-D 3,3' –T2 Deiodination of thyroxine 15 Therapeutic Agents 1. Thyroid Replacement Therapy 2. Antithyroid Drugs 16 1.Thyroid Replacement Therapy official in the old use Natural thyroid hormone preparations Desiccated thyroid preparations (Thyroid USP): acetone powder of bovine or porcine thyroid gland compressed into oral tablets ente of uniformity dusage a it Synthetic thyroid hormones ~ slow anset long duration , L-thyroxine: sodium salt T4 (25-300 mcg) Liothyronine sodium: crystalline T3 (rapid onset and Sodium Salt short duration) Liotrix: a mixture of the sodium salts of T4 and T3 in a 4:1 ratio result fast onset (from T3) & · in long duration (from T4) Use: treatment for hypothyroidism As you can see , modern dug still has a core of 73174. 17 SARs Gust downer +heineineisense : ring2 Only compounds with the appropriately substituted phenyl-X-phenyl nucleus have shown significant thyroid activities. Both single ring compounds (DIT) and its aliphatic and alicyclic ether derivatives showed no T4-like activity in the rat antigoiter test. voenenassnungent Hyroid gland wor agenmuserlands (TH aganist I HO I COOH T4 NH 2 I O I 18 SARs we can modify these structure Aliphatic side chain Alanine bearing ring (inner ring, -ring) Bridging atom Phenolic ring (outer ring, -ring) Phenolic hydroxy group  19 SARs: Aliphatic side chain 5 12 - : focus on carboxylate series HO R 5' I R1 cowier c G effect do antigoiter Jews I O I r americ potency Antigoiter Antigoiter No. R1 R5 No. R1 R5 Activity Activity standard 1 (L-T4) L-Ala I 100 8 CH2COOH H 36 2 (D-T4) D-Ala bisomer I 17 9 (CH2)2COOH I 15 greater than Ty 3 (L-T3) L-Ala Gisomer H H 550 10 (CH2)2COOH H 20 4 (D-T3) D-Ala 41 11 (CH2)3COOH I 4 5 COOH I 0.1 12 (CH2)3COOH H 5 focus 3 ethylamine 6 COOH H 0.4 13 (CH2)2NH2 I 0.6 an series 7 CH2COOH I 50 14 (CH2)2NH2 H 6 result : Mocaias ala disistenersden ins Cless potency 20 SARs: Aliphatic side chain L-isomers of T4 and T3 (cpd 1,3) are more potent than D- isomer (cpd 2,4) The carboxylate ion and the number of atoms connecting it to the ring are more important for activity. · optimum C is 2C In carboxylate series, the activity is maximum with the two- carbon acetic acid side chain (cpd 7,8) but decrease with shorter (cpd 5,6) or longer (cpd 9-12) The ethylamine side chain analogs of T4 and T3 (cpd 13,14) are less active than the corresponding carboxylic acid analogs (cpd 9,10)  Y resu It Ry R , inse rolaise ,des halogen : = · dete Haider allyt Jaredaussie dis 21 SARs: Inner ring R 5' HO R5 R1 V R 3' O R3 I Antigoiter No. R1 R3=R5 R3 R5 Activity Gonzoon eanians 15 L-Ala H I I