The resurgence of thyromimetics as lipid-modifying agents

Current Opinion in Investigational Drugs

Volumn 10, Issue 9, 2009, Pages 912-918

  Tancevski, I ^a   Eller, P ^a   Patsch, J R ^a   Ritsch, A ^a  

^a INNSBRUCK MEDICAL UNIVERSITY   (Austria)

Author keywords

Atherosclerosis; LDL receptor; Reverse cholesterol transport; Selective thyromimetic

Indexed keywords

( 3,5 DICHLORO 4 [( 4 HYDROXY 3 ISOPROPYLPHENOXY)PHENYL]ACETIC ACID; ( 3,5 DIIODOTHYROPROPIONIC ACID); ( 4 [ 3 [( 4 FLUOROPHENYL)HYDROXYMETHYL] 4 HYDROXYPHENOXY] 3,5 DIMETHYLPHENYL)MALONAMIC ACID SODIUM; 3 [ 3,5 DIBROMO 4 [ 4 HYDROXY 3 ( 1 METHYLETHYL)PHENOXY]PHENYL]AMINO 3 OXOPROPANOIC ACID; 3,5 DIBROMO 3' (2,3 DIHYDRO 3 OXO 6 PYRIDAZINYLMETHYL)THYRONINE; 3,5 DIMETHYL 4 [( 4 HYDROXY 3 ISOPROPYLBENZYL)PHENOXY]ACETIC ACID; 4 ( 3 CHLOROPHENYL) 2 (( 3,5 DIMETHYL 4 ( 4' HYDROXY 3' ISOPROPYLBENZYL)PHENOXY)METHYL) 2 OXIDO( 1,3,2 )DIOXAPHOSPHANANE; ACETIC ACID DERIVATIVE; ANTILIPEMIC AGENT; ATORVASTATIN; CGS 23425; DESSICATED THYROID HORMONE; DEXTROTHYROXINE; DITPA; EPROTIROME; GC 1; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; KAT 681; KB 141; KB 2115; LIOTHYRONINE; LOW DENSITY LIPOPROTEIN RECEPTOR; MALONIC ACID DERIVATIVE; MB 07811; N [ 3,5 DIMETHYL 4 ( 4' HYDROXY 3' ISOPROPYLPHENOXY)PHENYL]OXAMIC ACID; PHENOXYACETIC ACID DERIVATIVE; PHOSPHONIC ACID DERIVATIVE; PROPIONIC ACID; PROPIONIC ACID DERIVATIVE; SOBETIROME; T 0681; THYROID HORMONE DERIVATIVE; THYROID HORMONE RECEPTOR; THYROID HORMONE RECEPTOR BETA1; THYROMIMETIC AGENT; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ABSENCE OF SIDE EFFECTS; AMINOTRANSFERASE BLOOD LEVEL; ANGINA PECTORIS; ATHEROGENESIS; ATHEROSCLEROSIS; BODY WEIGHT; CARDIOTOXICITY; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL TRANSPORT; CLINICAL EVALUATION; CLINICAL TRIAL; CONGESTIVE HEART FAILURE; DESICCATION; DIARRHEA; DRUG DESIGN; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG MEGADOSE; DRUG SAFETY; DRUG SELECTIVITY; DRUG UPTAKE; DRUG WITHDRAWAL; ECHOGRAPHY; HUMAN; HYPERLIPIDEMIA; HYPERTHYROIDISM; HYPOTHYROIDISM; INSOMNIA; LIPID METABOLISM; LOW DRUG DOSE; NONHUMAN; PROTEIN EXPRESSION; RABBIT; RECEPTOR UPREGULATION; REVIEW; SIDE EFFECT; TACHYCARDIA; TREATMENT DURATION; TREATMENT RESPONSE; TRIACYLGLYCEROL BLOOD LEVEL;

ACETIC ACIDS; ANILIDES; ANIMALS; ANTICHOLESTEREMIC AGENTS; ANTILIPEMIC AGENTS; ARTERIOSCLEROSIS; ATHEROSCLEROSIS; BIOLOGICAL TRANSPORT; BIOMIMETICS; CHOLESTEROL, LDL; CLINICAL TRIALS AS TOPIC; DYSLIPIDEMIAS; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; LIPID METABOLISM; MALONATES; MOLECULAR STRUCTURE; PHENOLS; PHENYL ETHERS; PHENYLACETATES; PHOSPHONIC ACIDS; PROPIONIC ACIDS; PYRIDAZINES; RECEPTORS, LDL; THYROID GLAND; THYROID HORMONES;

EID: 69549084911     PISSN: 14724472     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (48)

1. Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, Orazem J, Magorien RD, O'Shaughnessy C, Ganz P: Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med (2005) 352(1):29-38. (Pubitemid 40075678)
2. Mason RL, Hunt HM, Hurxthal L: Blood cholesterol values in hyperthyroidism and hypothyroidism. N Engl J Med (1930) 203:1273-1278.
3. Moreno M, de Lange P, Lombardi A, Silvestri E, Lanni A, Goglia F: Metabolic effects of thyroid hormone derivatives. Thyroid (2008) 18(2):239-253. (Pubitemid 351271526)
4. Morkin E, Ladenson P, Goldman S, Adamson C: Thyroid hormone analogs for treatment of hypercholesterolemia and heart failure: Past, present and future prospects. J Mol Cell Cardiol (2004) 37(6):1137-1146. (Pubitemid 39585161)
5. Strisower B, Gofman JW, Galioni EF, Almada AA, Simon A: Effect of thyroid extract on serum lipoproteins and serum cholesterol. Metabolism (1954) 3(3):218-227.
6. Strisower B, Gofman JW, Galioni E, Rubinger JH, O'Brien GW, Simon A: Effect of long-term administration of desiccated thyroid on serum lipoprotein and cholesterol levels. J Clin Endocrinol Metab (1955) 15(1):73-80.
7. Galioni EF, Gofman JW, Guzvich P, Pouteau J, Rubinger JH, Strisower B: Long-term effect of dried thyroid on serum-lipoprotein and serum-cholesterol levels. Lancet (1957) 272(6960):120-123.
8. Jorgensen EC: Thyromimetics and antithyroid drugs. In: Berger's Medicinal Chemistry, Part III, 4th edition. Wolff ME (Ed), John Wiley & Sons Inc, New York, NY, USA (1979):103-145.
9. No authors listed: The coronary drug project: Findings leading to further modifications of its protocol with respect to dextrothyroxine. The coronary drug project research group. J Am Med Assoc (1972) 220(7):996-1008.
10. Young WF Jr, Gorman CA, Jiang NS, Machacek D, Hay ID: L-thyroxine contamination of pharmaceutical D-thyroxine: Probable cause of therapeutic effect. Clin Pharmacol Ther (1984) 36(6):781-787.
11. 4-treated individuals in a large clinical trial conducted as part of the NIH's Coronary Drug Project, which led to the discontinuation of this trial in the 1950s.
12. Leeson PD, Ellis D, Emmett JC, Shah VP, Showell GA, Underwood AH: Thyroid hormone analogues. Synthesis of 3′-substituted 3,5-diiodo-L-thyronines and quantitative structure-activity studies of in vitro and in vivo thyromimetic activities in rat liver and heart. J Med Chem (1988) 31(1):37-54. (Pubitemid 18027850)
13. Underwood AH, Emmett JC, Ellis D, Flynn SB, Leeson PD, Benson GM, Novelli R, Pearce NJ, Shah VP: A thyromimetic that decreases plasma cholesterol levels without increasing cardiac activity. Nature (1986) 324(6096):425-429. •• Described for the first time a novel selective thyromimetic (L-94901) with lipid-lowering properties, which did not have deleterious effects on the heart. (Pubitemid 17184157)
14. Tancevski I, Wehinger A, Demetz E, Duwensee K, Eller P, Schgoer W, Fievet C, Stellaard F, Rudling M, Patsch JR, Ritsch A: The novel thyromimetic KAT-681 promotes macrophage reverse cholesterol transport (RCT) in vivo and protects from atherosclerosis. Circulation (2007) 116(16 Suppl):II-298.
15. Tancevski I, Wehinger A, Demetz E, Hoefer J, Eller P, Huber E, Stanzl U, Duwensee K, Auer K, Schgoer W, Kuhn V et al: The thyromimetic T-0681 protects from atherosclerosis. J Lipid Res (2009) 50(5):938-944. •• Provides proof of concept that a selective thyromimetic compound can protect from the development of atherosclerosis.
16. Sap J, Munoz A, Damm K, Goldberg Y, Ghysdael J, Leutz A, Beug H, Vennstrom B: The c-erb-A protein is a high-affinity receptor for thyroid hormone. Nature (1986) 324(6098):635-640. (Pubitemid 17206350)
17. Weinberger C, Thompson CC, Ong ES, Lebo R, Gruol DJ, Evans RM: The c-erb-A gene encodes a thyroid hormone receptor. Nature (1986) 324(6098):641-646. (Pubitemid 17206351)
18. Apriletti JW, Ribeiro RC, Wagner RL, Feng W, Webb P, Kushner PJ, West BL, Nilsson S, Scanlan TS, Fletterick RJ, Baxter JD: Molecular and structural biology of thyroid hormone receptors. Clin Exp Pharmacol Physiol Suppl (1998) 25:S2-S11. (Pubitemid 28498841)
19. Lazar MA: Thyroid hormone receptors: Multiple forms, multiple possibilities. Endocr Rev (1993) 14(2):184-193. (Pubitemid 23118416)
20. Flamant F, Baxter JD, Forrest D, Refetoff S, Samuels H, Scanlan TS, Vennström B, Samarut J: International Union of Pharmacology. LIX. The pharmacology and classification of the nuclear receptor superfamily: Thyroid hormone receptors. Pharmacol Rev (2006) 58(4):705-711. (Pubitemid 44833740)
21. Gloss B, Trost S, Bluhm W, Swanson E, Clark R, Winkfein R, Janzen K, Giles W, Chassande O, Samarut J, Dillmann W: Cardiac ion channel expression and contractile function in mice with deletion of thyroid hormone receptor α or β. Endocrinology (2001) 142(2):544-550. (Pubitemid 32222402)
22. Johansson C, Vennström B, Thorén P: Evidence that decreased heart rate in thyroid hormone receptor-1-deficient mice is an intrinsic defect. Am J Physiol (1998) 275(2 Pt 2):R640-R646. (Pubitemid 28390140)
23. 3 regulation of cholesterol metabolism in mice. Mol Endocrinol (2002) 16(8): 1767-1777. •• Provides proof of concept that the TRβ1 isoform, mainly expressed in the liver, is responsible for the lipid-lowering activity of TH.
24. Metabasis Therapeutics Inc : Metabasis Therapeutics announces second quarter 2009 financial results. Press Release (2009): August 6. phx.corporate-ir.net/phoenix.zhtml?c=176272&p=irolnewsArticle& t=Regular&id=1318367&
25. Baxter JD, Webb P: Thyroid hormone mimetics: Potential applications in atherosclerosis, obesity and type 2 diabetes. Nat Rev Drug Discov (2009) 8(4):308-320. • Presents an important overview on the development of TH analogs.
26. Erion MD, Cable EE, Ito BR, Jiang H, Fujitaki JM, Finn PD, Zhang BH, Hou J, Boyer SH, van Poelje PD, Linemeyer DL: Targeting thyroid hormone receptor- agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index. Proc Natl Acad Sci USA (2007) 104(39):15490-15495. •• Describes an interesting approach that used HepDirect technology to enhance the hepatic targeting of the thyromimetic prodrug MB-07811 and its subsequent conversion into the active compound, a strategy that limits the generation of adverse events, such as the inhibition of the THA. (Pubitemid 47502944)
27. Taylor AH, Stephan ZF, Steele RE, Wong NC: 27. Beneficial effects of a novel thyromimetic on lipoprotein metabolism. Mol Pharmacol (1997) 52(3):542-547. (Pubitemid 27412981)
28. Grover GJ, Mellström K, Ye L, Malm J, Li YL, Bladh LG, Sleph PG, Smith MA, George R, Vennström B, Mookhtiar K et al: Selective thyroid hormone receptor- activation: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability. Proc Natl Acad Sci USA (2003) 100(17):10067-10072. (Pubitemid 37098262)
29. Grover GJ, Egan DM, Sleph PG, Beehler BC, Chiellini G, Nguyen NH, Baxter JD, Scanlan TS: Effects of the thyroid hormone receptor agonist GC-1 on metabolic rate and cholesterol in rats and primates: Selective actions relative to 3,5,3′-triiodo-L-thyronine. Endocrinology (2004) 145(4):1656-1661. (Pubitemid 38402372)
30. Ito BR, Zhang BH, Cable EE, Song X, Fujitaki JM, MacKenna DA, Wilker CE, Chi B, van Poelje PD, Linemeyer DL, Erion MD: Thyroid hormone receptor activation has additive cholesterol lowering activity in combination with atorvastatin in rabbits, dogs and monkeys. Br J Pharmacol (2009) 156(3):454-465. •• Presented data demonstrating for the first time that the combination of thyromimetics with statins can have an additive effect in reducing cholesterol levels.
31. Staels B, Van Tol A, Chan L, Will H, Verhoeven G, Auwerx J: Alterations in thyroid status modulate apolipoprotein, hepatic triglyceride lipase, and low density lipoprotein receptor in rats. Endocrinology (1990) 127(3):1144-1152. (Pubitemid 20277594)
32. Salter AM, Hayashi R, al-Seeni M, Brown NF, Bruce J, Sorensen O, Atkinson EA, Middleton B, Bleackley RC, Brindley DN: Effects of hypothyroidism and high-fat feeding on mRNA concentrations for the low-density-lipoprotein receptor and on acyl-CoA:cholesterol acyltransferase activities in rat liver. Biochem J (1991) 276(Pt 3):825-832.
33. Bakker O, Hudig F, Meijssen S, Wiersinga WM: Effects of triiodothyronine and amiodarone on the promoter of the human LDL receptor gene. Biochem Biophys Res Commun (1998) 249(2):517-521. (Pubitemid 28431785)
34. Berkenstam A, Kristensen J, Mellström K, Carlsson B, Malm J, Rehnmark S, Garg N, Andersson CM, Rudling M, Sjoberg F, Angelin B et al: The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans. Proc Natl Acad Sci USA (2008) 105(2):663-667. •• Described for the first time that the use of selective thyromimetics in humans is safe, and that selective thyromimetic treatment reduces plasma cholesterol levels, an effect associated with increased bile acid synthesis, similar to that observed in preclinical studies. (Pubitemid 351171765)
35. Soberitome: QuatRx Pharmaceuticals Co, Ann Arbor, MI, USA (2009). www.quatrx.com/clinical/431.htm
36. Eprotirome/KB2115: Karo Bio AB, Huddinge, Sweden (2009). www. karobio.com/en/Research - Development/Our-RD-Portfolio2/KB2115/
37. Cuchel M, Rader DJ: Macrophage reverse cholesterol transport: Key to the regression of atherosclerosis? Circulation (2006) 113(21):2548-2555. (Pubitemid 43948034)
38. Johansson L, Rudling M, Scanlan TS, Lundåsen T, Webb P, Baxter J, Angelin B, Parini P: Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol transport in euthyroid mice. Proc Natl Acad Sci USA (2005) 102(29):10297-10302. (Pubitemid 41024974)
39. Nilsson LM, Rehnmark S, Davoodpour P, Larsson L, Parini P: Thyroid hormone receptor modulation reduces the atherosclerotic process through increased reverse cholesterol transport. Arterioscler Thromb Vasc Biol (2009) 29(e9-e130):P325.
40. Zhang Y, Zanotti I, Reilly MP, Glick JM, Rothblat GH, Rader DJ: Overexpression of apolipoprotein A-I promotes reverse transport of cholesterol from macrophages to feces in vivo. Circulation (2003) 108(6):661-663. (Pubitemid 36999247)
41. Ritsch A, Patsch JR: Cholesteryl ester transfer protein: Gathering momentum as a genetic marker and as drug target. Curr Opin Lipidol (2003) 14(2):173-179. (Pubitemid 36521188)
42. Tanigawa H, Billheimer JT, Tohyama J, Zhang Y, Rothblat G, Rader DJ: Expression of cholesteryl ester transfer protein in mice promotes macrophage reverse cholesterol transport. Circulation (2007) 116(11):1267-1273. (Pubitemid 47517538)
43. Tancevski I, Frank S, Massoner P, Stanzl U, Schgoer W, Wehinger A, Fievet C, Eller P, Patsch JR, Ritsch A: Increased plasma levels of LDL cholesterol in rabbits after adenoviral overexpression of human scavenger receptor class B type I. J Mol Med (2005) 83(11):927-932. (Pubitemid 41598693)
44. Lin V, Klepp H, Hanley R: Sobetirome is a thyroid hormone receptor - and liver-selective thyromimetic that can effect substantial LDL-C lowering without significant changes in heart rate or the thyroid axis in euthyroid men. Abstr ENDO (2008) 90:OR36-OR33.
45. Pipeline: Core metabolic disease product candidates: Metabasis Therapeutics Inc, La Jolla, CA, USA (2009). www.mbasis.com/pipeline/metabolic- disease.html
46. Karo Bio AB: Successful KB2115 phase II study meets primary objectives. Press Release (2007): June 11. www.karobio.com/en/IR- -Media/Press-Releases/557/
47. Karo Bio AB: Karo Bio announces successful phase II study with eprotirome in combination with statin. Press Release (2008): August 4. www.karobio.com/en/IR - Media/Press-Releases/660/
48. Karo Bio AB: Successful phase II study expands the potential for eprotirome in dyslipidemia treatment. Press Release (2008): October 30. www.karobio.com/en/IR - Media/Press-Releases/681/