The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor β (THR-β) in the liver, while adverse effects, including cardiac effects, are mediated by thyroid hormone receptor α (THR-α). A pyridazinone series has been identified that is significantly more THR-β selective than earlier analogues. Optimization of this series by the addition of a cyanoazauracil substituent improved both the potency and selectivity and led to MGL-3196 (53), which is 28-fold selective for THR-β over THR-α in a functional assay. Compound 53 showed outstanding safety in a rat heart model and was efficacious in a preclinical model at doses that showed no impact on the central thyroid axis. In reported studies in healthy volunteers, 53 exhibited an excellent safety profile and decreased LDL cholesterol (LDL-C) and triglycerides (TG) at once daily oral doses of 50 mg or higher given for 2 weeks.

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7791 pyrany1oxy)dodecanoic acid, 1.38 1 g (3.15 mmol) of GPC-CdCIz, 0.854 g (7.0 mmol) of 4-(dimethylamino)pyridine, and 1.648 g (8.0 mmol) of dicyclohexylcarbodiimide was suspended in 15 mL of dry dichloromethane and stirred under nitrogen in the dark for 40 h. After removal of solvent in vacuo, the residue was dissolved in 50 mL of C H 3 0 H / H 2 0 (95/5, v/v) and stirred in the presence of 8.0 g of AG MP-50 (23 OC, 2 h) to allow for complete deprotection of the hydroxyl groups (monitored by thin-layer chromatography)." The resin was then removed by filtration and the solution concentrated under reduced pressure. The crude product (2.75 g). obtained after drying [12 h, 23 OC (0.05 mm)], was then subjected to chromatographic purification by using a 30-g (4 X 4 cm) silica gel column, eluting with solvents A and C, to yield 0.990 g (48%) of 2: Rf0.25 (solvent C); IR (KBr) uOH 3390, vc4 1728, Y~(~~~)~ 967, 1055, 1090 cm-I; 'H N M R (CD30D) 6 1.30-1.65 (br s, 36 H, CH20), 3.60-4.55 (m, 8 H, C H 2 0 , N(CH,)), 4.85 (s, 2 H, OH), 5.2 (m, 1 H, CH). Lipoic Acid Anhydride.12 A mixture of lipoic acid (1.03 g, 5.0 mmol) and dicyclohexylcarbodiimide (0.65 g, 3.0 mmol) was stirred in 15 mL of dry methylene chloride for 20 h at room temperature under a nitrogen atmosphere. The product mixture was filtered in order to remove the urea which had formed. Examination of the filtrate by IR revealed the presence of lipoic acid anhydride (1735 and 1805 cm-I) and the absence of the parent carboxylic acid (vC4 1701 cm-I). This solution was used directly in the synthesis of 1 described below. 1,2-Bis[12-(lipoyloxy)dodecanoyl]-sn-glycero-3-phosphocholine (1). 1,2-Bis( 12-hydroxydodecanoyl)-sn-glycero-3-phosphocholine (0.04 g, 0.06 mmol) was added to 2.0 mL of a 0.15 M solution of lipoic acid containing 16 mg (0.1 3 mmol) of 4-(dimethy1amino)pyridine. After the mixture was stirred for 6 h under nitrogen at room temperature, thin-layer chromatography (silica, solvent C) indicated complete conversion to 1. The CHI), 2.32 (t, 4 H, CH,C=O), 3.22 ( s , 9 H, N(CH,),), 3.52 (t, 4 H, (11) Beier, R.; Mundy, B. P. Synth. Commun. 1979, 9, 271. (12) Nambu, N.; Endo, T.; Okawara, M. J. Polym. Sci., Chem. Ed. 1980, 18, 2793.product mixture was then filtered and concentrated under reduced pressure. The residue was dissolved in 5 mL of solvent B and passed through a 1.2 X 1.5 cm AG MP-50 cation-exchange column in order to remove 4-(dimethylamino)pyridine. The filtrate was concentrated under reduced pressure, dissolved in a minimum volume of absolute ethanol, and then concentrated again. Chromatographic purification of the residue on a silica gel column (0.9 X 6 cm), eluting first with solvent A and then with solvent C (compound 1 elutes on silica as a single yellow band), afforded, after drying [ I O h, 22 OC (0.05 mm)], 0.055 g (90%) of 1 as a yellow solid: R 0.45 (solvent C); IR (KBr) ucz0 1732, uN(cH3)3 970, 1050, 1090cm-'; H NMR (CDCI,) 6 1.25 (s 28 H, CH2), 1.40-2.05 (m, Abstract: Allenol silyl ethers 1 with various substitution patterns were prepa...

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