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Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 15, 2009, Pages 4159-4166

Novel and potent inhibitors of stearoyl-CoA desaturase-1. Part II: Identification of 4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide and its biological evaluation

(16) Uto, Yoshikazu a Ogata, Tsuneaki a Kiyotsuka, Yohei a Miyazawa, Yuriko a Ueno, Yuko a Kurata, Hitoshi a Deguchi, Tsuneo a Yamada, Makiko a Watanabe, Nobuaki a Takagi, Toshiyuki a Wakimoto, Satoko a Okuyama, Ryo a Konishi, Masahiro a Kurikawa, Nobuya a Kono, Keita a Osumi, Jun a

a DAIICHI SANKYO CO (Japan)

Author keywords

Desaturation index; SCD 1 inhibitors; Thiazole

Indexed keywords

4 ETHYLAMINO 3 (2 HYDROXYETHOXY) N [5 (3 TRIFLUOROMETHYLBENZYL)THIAZOL 2 YL]BENZAMIDE; 4 ETHYLAMINO 3 [2 (TETRAHYDROPYRAN 2 YLOXY)ETHOXY]BENZOIC ACID; ACYL COENZYME A DESATURASE; ACYL COENZYME A DESATURASE 1; ENZYME INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DISTRIBUTION VOLUME; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; IC 50; MALE; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; AREA UNDER CURVE; BENZAMIDES; CHEMISTRY, PHARMACEUTICAL; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; INHIBITORY CONCENTRATION 50; MICE; MICE, INBRED C57BL; MODELS, CHEMICAL; STEAROYL-COA DESATURASE; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES;

MURINAE; MUS;

EID: 67649993588 PISSN: 0960894X EISSN: None Source Type: Journal
DOI: 10.1016/j.bmcl.2009.05.123 Document Type: Article

Times cited : (28)

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11
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- Compound 13 was prepared as follows: 5-(3-Trifluoromethylbenzyl, 1,3,4]thiadiazol-2-ylamine (9, A mixture of (α,α,α-trifluoro-m-tolyl)acetic acid (8, 1.15 g, 6.12 mmol, thiosemicarbazide (1.15 g, 12.6 mmol, BOP reagent (3.24 g, 7.33 mmol, and Et3N (1.7 mL, 12 mmol) in anhydrous THF (20 mL) was stirred at room temperature for 20 h. The reaction mixture was concentrated, diluted with H2O and extracted with EtOAc (twice, The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4, and concentrated. The off-white solid thus obtained (1.72 g) was mixed with methanesulfonic acid (0.48 mL, 7.4 mmol) and toluene (20 mL, The suspension was heated to reflux for 4 h and cooled to room temperature. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 (×2) and brine, dried Na2SO4, and concentrated. Chromatography of
- +.

12
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- 3-(2-Hydroxyethoxy)-4-methoxy-N-[5-(3-trifluoromethylbenzyl, 1,3,4]thiadiazol-2-yl]benzamide (13, A solution of 9 (100 mg, 0.386 mmol, 3-(2-hydroxyethoxy)-4-methoxybenzoic acid (83 mg, 0.39 mmol, HATU (178 mg, 0.468 mmol, and Et3N (90 μL, 0.65 mmol) in DMA (2 mL) was stirred at room temperature for four days. After work-up, the crude product was purified by chromatography on SiO2 (CH2Cl2/MeOH 20:1) and subsequent recrystallization (2-PrOH) to give 29 mg (17, of 13 as a white solid:1H NMR(400 MHz, DMSO-d6, δ 12.8 (1H, br s, 7.76 (3H, d, J, 9.8 Hz, 7.68 (2H, dd, J, 8.1 and 8.1 Hz, 7.61 (1H, dd, J, 7.8 and 7.8 Hz, 7.62 (1H, d, J, 7.9 Hz, 4.88 (1H, t, J, 5.2 Hz, 4.52 (2H, s, 4.07 (2H, t, J, 4.9 Hz, 3.85 (3H, s, 3.76 (2H, dt, J, 4.8 and 4.9 Hz, MS (ESI) m/z: 454 M+H
- +.

13
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15
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- note
- 14C] C18:4n - 3.

16
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- note
- 14C] stearate.

17
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- Compound 37c was prepared as follows: 4-Amino-3-[2-(tetrahydropyran-2-yloxy)ethoxy]benzoic acid methyl ester (34, A suspension of 3-hydroxy-4-nitro-benzoic acid ethyl ester (33, 5.02 g, 25.5 mmol, 2-(2-bromoethoxy)tetrahydro-2H-pyran (5.8 mL, 38 mmol, K2CO3 (7.04 g, 50.9 mmol) in DMA (70 mL) was heated at 80 °C for 5 h, cooled to room temperature, and extracted with EtOAc. The organic layer was washed with H2O (×4) and brine, dried (Na2SO4, and concentrated. Chromatography of the residue on SiO2 (hexanes/EtOAc 17:3-1:1) to give 8.50 g of the alkylated compound as a yellow oil: 1H NMR(400MHz,CDCl3, δ 7.84 (1H, s, 7.83 (1H, d, J, 9.8 Hz, 7.71 (1H, d, J, 9.7 Hz, 4.73 (1H, t, J, 3.3 Hz, 4.42-4.34 (2H, m, 4.16-4.08 (1H, m, 3.97 (3H, s, 3.92-3.83 (2H, m, 3.57-3.52 (1H, m, 1.86-1.71 (2H, m, 1.65-1.51 (4H, m, A suspension of the yellow oil (8.50 g, 25.5 mmol) and Pd/C 10
- +.

18
- 67649951404
- 4-Ethylamino-3-[2-(tetrahydropyran-2-yloxy)ethoxy]benzoic acid (35c, To a solution of 34 (4.45 g, 15.3 mmol) in THF/MeOH (2:1, 90 mL) were successively added acetic acid (0.88 mL, 15 mmol, acetaldehyde (4.3 mL, 77 mmol) and sodium cyanoborohydride (2.89 g, 46.0 mmol) at 0 °C. To complete the reaction, additional amounts of the reagents were added and the reaction was heated to 60 °C. The reaction mixture was concentrated, diluted with EtOAc and saturated aqueous NaHCO3. The separated organic layer was washed with water and brine, dried (Na2SO4, and concentrated. Chromatography of the residue on SiO2 (CH2Cl2/EtOAc, and then CH2Cl2/MeOH) gave 3.19 g (64, of the monoalkylated compound as a colorless oil and 1.63 g (30, of the dialkylated compound as a colorless oil. To a solution of the monoalkylated compound (514 mg, 1.59 mmol) in 1,4-dioxane (10 mL) was added 1 N NaOH (2.4 mL) at room te
- +.

19
- 67649976276
- 4-Ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide (37c, A solution of 21 (95 mg, 0.37 mmol, 35c (114 mg, 0.369 mmol, HATU (154 mg, 0.405 mmol, and Et3N (0.10 mL, 0.74 mmol) in DMA (6 mL) was heated at 70 °C for 3 days. The reaction mixture was diluted with EtOAc and citric acid (aq, The separated organic layer was washed with H2O (×3) and brine, dried (Na2SO4, and concentrated. Chromatography of the residue on SiO2 (KP-NH, 40-75 μm, 100A, Biotage, hexanes/CH2Cl2 3:7 to 0:1) gave 122 mg (60, of the amide compound as a pale yellow oil. To a solution of the amide (122 mg, 0.221 mmol) in MeOH (10 mL) was added 1 N HCl 0.55 mL, The reaction mixture was heated at 50 °C for 1.5 h and concentrated. The residue was diluted with CH2Cl2, iPr2O, hexanes and saturated aqueous NaHCO3. The resulting precipitate was colle
- +.

20
- 33845590381
- Flowers M.T., Groen A.K., Oler A.T., Keller M.P., Choi Y.J., Schueler K.L., Richards O.C., Lan H., Miyazaki M., Kuipers F., Kendziorski C.M., Ntambi J.M., and Attie A.E. J. Lipid Res. 47 (2006) 2668
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- Flowers, M.T.¹ Groen, A.K.² Oler, A.T.³ Keller, M.P.⁴ Choi, Y.J.⁵ Schueler, K.L.⁶ Richards, O.C.⁷ Lan, H.⁸ Miyazaki, M.⁹ Kuipers, F.¹⁰ Kendziorski, C.M.¹¹ Ntambi, J.M.¹² Attie, A.E.¹³

21
- 67649976278
- note
- 50.

22
- 67649960967
- note
- 2O and extracted with 1 mL n-hexane. One microliter of the final hexane extracts was loaded to a gas chromatogram to determine the stearate and oleate content. The desaturation index was calculated as the ratio of oleate to stearate.

23
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- Miyazaki, M.¹ Man, W.C.² Ntambi, J.M.³

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