Novel peroxisome proliferator-activated receptor ligands for Type 2 diabetes and the metabolic syndrome

Expert Opinion on Investigational Drugs

Volumn 12, Issue 9, 2003, Pages 1489-1500

  Miller, Anne R ^a   Etgen, Garret J ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

Diabetes; PPAR; Syndrome X; TZD

Indexed keywords

2 [4 [2 (5 TETRAZOLYLMETHYL)BENZYLOXY]PHENOXYMETHYL]QUINOLINE; 2,2 DICHLORO 12 (4 CHLOROPHENYL)DODECANOIC ACID; 5 (2,4 DIOXO 5 THIAZOLIDINYLMETHYL) 2 METHOXY N [4 (TRIFLUOROMETHYL)BENZYL]BENZAMIDE; 5 [4 [2 (1 INDOLYL)ETHOXY]BENZYL] 2,4 THIAZOLIDINEDIONE; [2 METHYL 4 [4 METHYL 2 (4 TRIFLUOROMETHYLPHENYL) 5 THIAZOLYLMETHYLTHIO]PHENOXY]ACETIC ACID; ANTIDIABETIC AGENT; CLX 0921; FARGLITAZAR; GW 0072; IMIGLITAZAR; INSULIN; L 764406; LY 3692; MIFOBATE; N (2 BENZOYLPHENYL) O [2 (METHYL 2 PYRIDINYLAMINO)ETHYL]TYROSINE; NETOGLITAZONE; NIP 221; NIP 223; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PIOGLITAZONE; R 483; RAGAGLITAZAR; RECEPTOR SUBTYPE; ROSIGLITAZONE; T 131; THIAZOLIDINE DERIVATIVE; TROGLITAZONE; UNCLASSIFIED DRUG; UNINDEXED DRUG; YM 440;

CLINICAL TRIAL; DISEASE ASSOCIATION; DOSE RESPONSE; DRUG EFFICACY; DRUG POTENCY; DRUG SAFETY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TOLERABILITY; FLUID RETENTION; GLUCOSE TOLERANCE; HUMAN; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIVER TOXICITY; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PROTEIN FAMILY; PROTEIN TARGETING; REVIEW; STRUCTURE ACTIVITY RELATION; WEIGHT GAIN;

DIABETES MELLITUS, TYPE 2; HUMANS; LIGANDS; METABOLIC SYNDROME X; RECEPTORS, CYTOPLASMIC AND NUCLEAR; TRANSCRIPTION FACTORS;

EID: 0141517123     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543784.12.9.1489     Document Type: Review

References (101)

1. KING H, REWERS M: Global estimates for the prevalence of diabetes mellitus and impaired glucose tolerance in adults. Diabetes Care (1993) 16:157-177.
2. SCHNEDL WJ, LIEBMINGER A, ROLLER R et al.: Hemoglobin variants and determination or glycated hemoglobin (HbA1c). Diabetes Metab. Res. Rev. (2001) 17:94-98.
3. REAVEN GM: Syndrome X: 6 years later. J. Intern. Med. (1994) (Suppl. 736):13-22.
4. BRINTON EA. Lipid abnormalities in the metabolic syndrome. Curr. Diab. Rep. (2003) 3(1):65-72.
5. MCVEIGH GE, COHN JN: Endothelial dysfunction and the metabolic syndrome. Curr. Diab. Rep. (2003) 3(1):87-92.
6. VIRGIN SE, SCHMITKE JA: Metabolic syndrome. AAOHN J. (2003) 51(1):28-37.
7. REAVEN GM: Pathophysiology of insulin resistance in human disease. Physiol. Rev. (1995) 75(3):473-486.
8. VOSPER H, KHOUDOLI GA, GRAHAM TL et al.: Peroxisome proliferator-activated receptor agonists, hyperlipidaemia, and atherosclerosis. Pharmacol. Ther. (2002) 95(1):47-62.
9. BERGER J, WAGNER JA: Physiological and therapeutic roles of peroxisome proliferator-activated receptors. Diabetes Technol. Ther. (2002) 4(2):163-174.
10. ISSEMANN I, GREEN S: Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature (1990) 347:645-650.
11. DREYER C, KREY G, KELLER H et al.: Control of the peroxisomal β-oxidation pathway by a novel family of nuclear hormone receptors. Cell (1992) 68:879-887.
12. ZHU Y, ALVARES K, QIN H et al.: Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver. J. Biol. Chem. (1993) 268:26817-26820.
13. TONTONOZ P, HU E, GRAVES R et al.: mPPARγ2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. (1994) 8:1224-1234.
14. KLIEWER SA, FORMAN BA, BLUMBERG B et al.: Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc. Natl. Acad. Sci. USA (1994) 91:7355-7359.
15. BERGER J, MOLLER DE: The Mechanism of action of PPARs. Ann. Rev. Med. (2002) 53:409-435.
16. KLIEWER SA, XU HE, LAMBERT MH et al.: Peroxisome proliferator-activated receptors: from genes to physiology. Rec. Prog. Horm. Res. (2001) 56:239-263.
17. SEEDORF U, ASSMANN G: The role of PPARα in obesity. Nat. Metab. Cardiovasc. Dis. (2001) 11:189-194.
18. ROSEN ED, SPIEGELMAN BM: PPARγ: a nuclear receptor of metabolism, differentiation, and cell growth. J. Biol. Chem. (2001) 276:37731-37734.
19. WILSON TM, BROWN PJ, STERNBACH DD et al.: The PPARs: from orphan receptors to drug discovery. J. Med. Chem. (2000) 43:527-550.
20. FORMAN BM, CHEN J, EVANS RM: Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ Proc. Natl. Acad. Sci. USA (1997) 94:4312-4317.
21. OLIVER WR Jr, SHENK JL, SNATH JL et al.: A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport. Proc. Natl. Acad. Sci. USA (2001) 98:5306-5311.
22. WANG Y-W, LEE C-H, TIEP S et al.: Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell (2003) 113:159-170.
23. KLIEWER SA, WILSON TM: The nuclear receptor PPARγ - bigger than fat. Curr. Opin. Genet. Dev. (1998) 8:576-581.
24. WARNER-LAMBERT CO.: Warner-Lambert voluntarily discontinues the sale of Rezulin (2000) (Press release).
25. ARONOFF S, ROSEBLATT S, BRAITHWAITE S et al.: Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with Type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. Diabetes Care (2000) 23:1605-1611.
26. ROSENBLATT S, MISKIN B, GLAZER B et al.: The impact of pioglitazone on glycemic control and atherogenmic dyslipidemia in patients with Type 2 diabetes mellitus. Coron. Artery Dis. (2001) 12:413-423.
27. WAGSTAFF AJ, GOA KL: Rosiglitazone. A review of its use in the management of Type 2 diabetes mellitus. Drugs (2002) 62:1805-1837.
28. PHILLIPS LS, GRUNBERGER G, MILLER E et al.: Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with Type 2 diabetes. Diabetes Care (2001) 24:308-315.
29. LEBOVITZ HE, DOLE JF, PATWARDHAN R et al.: Rosiglitazone monotherapy is effective in patients with Type 2 diabetes. J. Clin. Endocrinol. Metab. (2001) 86:280-288.
30. MARTENS FMAC, VISSEREN FLJ, LEMAY J et al.: Metabolic and additional vascular effects of thiazolidinediones. Drugs (2002) 62:1463-1480.
31. UPTON P. WIDDOWSON PS, KADOWAKI S et al.: Improved insulin sensitivity in Zucker and ZDF rats following chronic treatment with novel thiazolidinedione MCC-555. Br. J. Pharmacol. (1997) 122(Proc. Suppl.): 149P.
32. ISHII S, WASAKI M, OHE T et al.: MCC-555: a highly potent thiazolidinedione lacking hematological and cardiac side-effects. Diabetes (1996) 45(Suppl. 2):141A.
33. Mitsubishi licenses antidiabetic to J & J. Pharma Japan (1998) 1621:13.
34. ISHII S, HIKE N. YOSHIDA T: The improving effect of MCC-555, an insulin sensitizer, on glucose tolerance in obese cynomolgus monkeys. Diabetes (1999) 48(Suppl. 1):A452-A453.
35. ARAKI K, YACHI M, HAGISAWA Y et al.: Antidiabetic characterization of CS-011: a new thiazolidinedione with potent insulin-sensitizing activity. Diabetes (2000) 49(Suppl. 1):A105.
36. PULASKI JT, DAVIS JA, YUILLE K et al.: The antidiabetic effects of CI-1037/CS011, a new thiazolidinedione. Diabetes (2000) 49(Suppl. 1):A122.
37. SANKYO CO. LTD: Drug development pipeline: gemfibrozil, azeinidipine, CS-834, CS-940, MM-801, CS-891, CS-891B, CS-615, CS-747, CS-682, CS-780, CS-011, cadrofloxican, oxybutynin, transdermal, TheraTech. (1999) (Company Communication).
38. MEDICHERIA. S, DEY D, NEOGI P et al.: CLX-0921: A new PPAR-gamma agonist anti-diabetic thiazolidinedione compound. Diabetes (2000) 49(Suppl. 1):475-P.
39. NESCHEN S, BRUNMAIR B, RODEN M et al.: The thiazolidinedione BM-13.1258 insulin-independently increases muscle glucose oxidation in obese rats. Diabetologia (1998) 41(Suppl. 1):A186.
40. BRUNMAIR B, GRAS F, NESCHEN S et al.: Direct thiazolidinedione action on isolated rat skeletal muscle fuel handling is independent of peroxisome proliferator-activated receptor-γ-mediated changes in gene expression. Diabetes (2001) 50:2309-2315.
41. GOWRI MS: Orally active, synthetic antidiabetic compounds derived from medicinal plants. SMI Conference, Frankfurt am Main, Germany (2002).
42. ROCHE HOLDING AG. (2001) (Presentation to investors).
43. NAITOH T, NAKABEPPU H, TAKESHI Y et al.: NIP-221 is a novel and potent thiazolidinedione-based peroxisome proliferator-activated receptor (PPAR)γ ligand with long biological half-time. Diabetes (2000) 49(Suppl. 1):A118.
44. NAITOH T, KAMON J, YOTSUMOTO T et al.: NIP-223 is a novel and potent thiazolidinedione-based peroxisome proliferator-activated receptor (PPAR)-gamma ligand. Diabetes (2000) 49(Suppl. 1):481-P.
45. LOHRAY BB, BHUSHAN V, RAO BP et al.: Novel euglycemic and hypolipidemic agents. J. Med. Chem. (1998) 41(10):1619-1630.
46. LOHRAY BB, BHUSHAN V, BHEEMA RP et al.: Novel indole containing thiazolidinedione derivatives as potent euglycemic and hypolipidaemic agents. Bioorg. Med. Chem. Lett. (1997) 7(7):785-788.
47. ANIMATI F, ARCAMONE F, BIGIONI M et al.: Biochemical and pharmacological activity of novel 8-fluoroanthracyclines: influence of stereochemistry and conformation. Mol. Pbarmacol. (1996) 50:603-09.
48. BROWN KK, HENKE BR, BLANCHARD SD et al.: A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat. Diabetes (1999) 48:1415-1424.
49. LIU KG, LAMBERT MH, AYSCUE AH et al.: Synthesis and biological activity of L-tyrosine-based PPARgamma agonists with reduced molecular weight. Bioorg. Med. Chem. Lett. (2001) 11(24):3111-3113.
50. TULARIK, INC.: Tularik begins Phase I clinical trial of T131, a novel insulin sensitizer for the treatment of Type 2 diabetes (2003) (Press release).
51. IMOTO H, SUGIYAMA Y. KIMURA H et al.: Studies on non-thiazolidinedione antidiabetic agents. 2. Novel oxyiminoalkanoic acid derivatives as potent glucose and lipid lowering agents. Chem. Pharm. Bull. (2003) 51(2):138-151.
52. 4 antagonist and pharmacokinetics in rats. 209th American Chemical Society Meeting, Anaheim, CA, USA (1995):MEDI 215 (Abstract).
53. BROOKS CDW, SUMMERS JB: Modulator of leukotriene biosynthesis and receptor activation. J. Med. Chem. (1996) 39(14):2629-2654.
54. STEVENS JC, FAYER JL, CASSIDY KC: Characterization of 2-[[4-[[2-(1H-tetrazol-5-ylmethy)phenyl] methoxy]methyl]quinoline N-glucuronidation by in vitro and in vivo approaches. Drug Metab. Dispos. (2001) 29(3):289-295.
55. PILL J, NAKAYAMA M, BODKIN NL et al. Lipid modulating and antidiabetic potency of the PPARα activators BM 17.074 and Bezafibrate. PPARs: from Basic Science to Clinical Applications, Florence, Italy (2001):6.
56. AASUM E, BELKE DD, SEVERSON DL et al.: Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM17.0744, a novel ppar-α activator. Am. J. Pbysiol. Heart Circ. Physiol. (2002) 283:H949-H957.
57. SCHAFER S, BODKIN NL, HANSEN BC et al.: Metabolic alteration induced by K-111, a PPAR activator, in non-human Primates. PPARs: Transcriptional Regulators of Metabolism and Metabolic Disease, Keystone, CO, USA (2003):306.
58. WANG X, BARR RJ, BEAN JS et al.: Synthesis and SAR studies toward the selective PPARα agonist LY518674. ACS 224th National Meeting, Boston, USA (2002):MEDI 363 (Abstract).
59. LEIBOWITZ MD, FIEVET C, HENNUYER N et al.: Activation of PPARδ alters lipid metabolism in db/db mice. FEBS Lett. (2000) 473:333-336.
60. MURAKAMI K, TOBE K, IDE T et al.: A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: effect of PRAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats. Diabetes (1998) 47:1841-1847.
61. MURAKAMI K, TSUNODA M, OHASHI M et al.: Amelioration by KRP-297, a new thiazolidinedione, of impaired glucose uptake in skeletal muscle from obese insulin-resistant animals. Metabolism (1999) 48(11):1450-1454.
62. SORBERA LA, LEESON PA, MARTIN L et al.: Farglitazar. GI-262570. Drug Future (2001) 26:354-363.
63. O'CONNOR SEMMES R, MYDLOW P, WALKER A et al.: GI 262570, A PPAR-gamma agonist, maintains metabolic improvements throughout 24 hour profile in Type 2 diabetic patients. Diabetes (2000) (Suppl. 1):A119 (Press release).
64. EDWARDS RC, KLER L, MCNEIL SJ et al.: GI 262570, a tyrosine-based PPAR-gamma agonist, reduces triglycerides and increases HDL-C concentrations in patients with Type 2 diabetes mellitus when combined with glibenclamide treatment. Diabetes (2000) 49(Suppl. 1):A104-A105.
65. WILLSON TM, COLLINS JL, HENKLE BR et al.: PRAR agonists for metabolic diseases. 220th ACS Meeting, Washington, DC (2000):MEDI 197.
66. CRONET P, PETERSEN JFW, FOLMER R et al.: Structure of the PPARα and -γ ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family. Structure (2001) 9:699-706.
67. OAKES N, KJELLSTEDT A, THAL P et al.: AZ 242, a novel PPAR[alpha]/[gamma] agonist, enhances the severely impaired metabolic flexibility and insulin action in skeletal muscle of obese Zucker rats. Diabetes (2002) 51 (Suppl. 2):A110.
68. ROSENGREN B, CARINA H, EVA HC et al.: AZ 242, a novel PPAR[alpha]/[gamma] agonist, improves the hdl-mediated efflux of cholesterol from differentiated, triglyceride-overloaded THP-1 monocytes. Diabetes (2002) 51(Suppl. 2):A143.
69. LOHRAY BB, LOHRAY VB, BAJJI AC et al.: (-)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid [(-)DRF 2725]: a dual PPAR agonist with potent antihyperglycemic and lipid modulating activity. J. Med. Chem. (2001) 44:2675-2678.
70. CHENG PT, CHANDRASENA G, CHEN S et al.: BMS-298585 is a novel, uniquely balanced dual activator of peroxisome proliferator activated receptors (PPAR) alpha and gamma, with an excellent ADME profile. Diabetes (2002) 51(Suppl. 2):A94.
71. NOVO NORDISK A/S: Novo Nordisk suspends the clinical development of Ragaglitazar. (2002) (Press release).
72. REIFEL-MILLER A, WARSHAWSKY A, ARDECKY R et al.: LY519818: a novel non-TZD, PPARγ-dominant agonist with improved insulin sensitization and unique co-factor recruitment and response element activation profiles. Diabetes (2003) 52(Suppl. 1):A143.
73. ETGEN GJ, BRODERICK CL, OLDHAM BA et al.: LY510929: a novel highly potent PPARα,γ dual agonist for the treatment of Type 2 diabetes and associated dyslipidemia. Diabetes (2003) 52(Suppl. 1 ):A141.
74. ETGEN GJ, OLDHAM BA, JOHNSON WT et al.: A tailored therapy for the metabolic syndrome. The dual peroxisome proliferator-activated receptor-α/γ agonist LY465608 ameliorates insulin resistance and diabetic hyperglycemia while improving cardiovascular risk factors in preclinical models. Diabetes (2002) 51:1083-1087.
75. ETGEN GJ, MANTLO N: PPAR ligands for metabolic disorders. Curr. Top. Med. Chem. (2003) (In press).
76. LIU KG, LAMBERT MH, LEESNITZER LM et al.: Identification of a series of PPARγ/δ dual agonists via solid-phase parallel synthesis. Bioorg. Med. Chem. Lett. (2001) 11:2959-2962.
77. OLIVER WR, RAFFERTY S, BODKIN NL et al.: Simultaneous activation of the three peroxisome proliferator-activated receptors (PPAR) subtypes with a PPARpanTM agonist improves insulin resistance and symptoms associated with metabolic syndrome in obese hyperglycemic rhesus monkeys. Diabetes (2003) 52(Suppl. 1):A129.
78. BERGER J, LEIBOWITZ MD, DOEBBER TW et al.: Novel peroxisome proliferator-activated receptor (PPAR) γ and PPARδ ligands produce distinct biological effects. J. Biol. Chem. (1999) 274:6718-6725.
79. MCDONNELL D, CLEMM D, HERMANN T et al.: Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Mol. Endocrinol. (1995) 9(6):659-669.
80. OBERFIELD JL, COLLINS JL, HOLMES CP et al.: A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation. Proc. Natl. Acad. Sci. USA (1999) 96(11):6102-6106.
81. ROCCHI S, PICARD F, VAMECQ J et al.: A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity. Mol. Cell (2001) 8(4):737-747.
82. BERGER JP, PETRO AE, MACNAUL KL et al.: Distinct properties and advantages of a novel PPARgarnma selective modulator. Mol. Endocrinol. (2003) 17(4):662-676.
83. ELBRECHT A, CHEN Y, ADAMS A: L-764406 is a partial agonist of human peroxisome proliferator-activated receptor γ. J. Biol. Chem. (1999) 274(12):7913-7922.
84. KUROSAKI E, NAKANO R, SHIMAYA A et al.: Differential effects of YM440 a hypoglycemic agent on binding to a peroxisome proliferator-activated receptor γ and its transactivation. Biochem. Pharmacol. (2003) 65:795-805.
85. SHIMAYA A, KUROSAKI E, NAKANO R et al.: The novel hypoglycemic agent YM440 normalizes hyperglycemia without changing body fat weight in diabetic db/db mice. Metabolism (2000) 49(3):411-417.
86. DRAGOMIR K, IONESCUTRGOVISTE CI, ROSENTHAL A et al.: Balaglitazone, a new thiazolidinedione, improves glucose and lipid control in patients with Type 2 diabetes. Diabetes (2003) 52(Suppl. 1):530P.
87. CHAKRABARTI R, VIKRAMADITHYAN R, MISRA P et al.: Balaglitazone, a quinazalone analogue of thiazolidinedione shows excellent antidiabetic and hypolipidemic potential with less adipogenic activity. Diabetes (2003) 52(Suppl. 1):601P.
88. WULFF E, PEDERSEN K, SAUERBERG P: Balaglitazone a new partial PPARγ agonist has a better cardio vascular safety profile and glycemic control compared with the full PPARγ agonist rosiglitazone. Diabetes (2003) 52(Suppl. 1):594P.
89. REGINATO MJ, BAILEY ST, KRAKOW SL et al.: A potent antidiabetic thiazolidinedione with unique peroxisome proliferator-activated receptor gamma-activating properties. J. Biol. Chem. (1998) 273(49):32679-32684.
90. CAMP H, OU L, WISE SC et al.: Differential activation of peroxisome proliferator-activated receptor-γ by troglitazone and rosiglitazone. Diabetes (2000) 49(4):539-547.
91. FONSECA V, FOYT HL, SHEN K et al.: Long-term effects of troglitazone: open-label extension studies in Type 2 diabetic patients. Diabetes Care (2000) 23(3):354-359.
92. HORIKOSHI H, HASHIMOTO T, FUJIWARA T: Troglitazone and emerging glitazones: new avenues for potential therapeutic benefits beyond glycemic control. Prog. Drug Res. (2000) 54:191-212.
93. SUNAYAMA S, WATANABE Y, OHMURA H et al.: Effects of troglitazone on atherogenic lipoprotein phenotype in coronary patients with insulin resistance. Atherosclerosis (1999) 146(1):187-193.
94. KAWAI T, TAKEI I, OGUMA Y et al.: Effects of troglitazone on fat distribution in the treatment of male Type 2 diabetes. Metabolism (1999) 48(9):1102-1107.
95. CHEAH JS: Management of obesity in non-insulin-dependent diabetes mellitus. Asia Pacific J. Clin. Nutrition (1998) 7(3/4):282-286.
96. RIEUSSET J, TOURI F, MICHALIK L et al.: A new selective peroxisome proliferator-activated receptor gamma antagonist with antiobesity antidiabetic activity. Mol. Endocrinol. (2002) 16(11):2628-2644.
97. MUKHERJEE R, HOENER PA, JOW L et al.: A selective peroxisome proliferator-activated receptor γ (PPARγ) modulator blocks adipocyte differentiation but stimulates glucose uptake in 3T3-L1 adipocytes. Mol. Endocrinol. (2000) 14(9):1425-1433.
98. AL-SHAMMA H, CARTER B, CHEN Q et al.: Inhibitor of PPARgamma activity displays anti-diabetic and anti-dyslipidemic action in vivo. Diabetes (2001) 50(Suppl. 2):A105.
99. LALA DS, MUKHERJEE R, SCHULMAN IG et al.: Activation of specific RXR heterodimers by an antagonist of RXR homodimers. Natyre (1996) 383(6599):450-453.
100. MICHELLYS PY, ARDECKY RJ, CHEN JH et al.: Novel (2E,4E,6Z)-7-(2-alkoxy-3,5-dialkylbenzene)-3-methylocta-2,4,6-trienoic acid retinoid X receptor modulators are active in models of Type 2 diabetes. J. Med. Chem. (2003) 46(13):2683-2696.
101. REIFEL-MILLER A, ARDECKY RJ, BOEHM MF et al: Selective RXR modulators: improvements over RXR agonists for the treatment of Type 2 diabetes. In: PPARs: Transcriptional Regulators of Metabolism and Metabolic Diseas, Keystone, CO, USA (2003):141.