Y. Uto et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4151–4158
4157
Table 7
D.; Kym, P. R.; Suhar, T. S.; Smith, H. T.; Cao, N.; Yang, R.; Janis, R. S.; Krauser, J.
A.; Cepa, S. P.; Beno, D. W. A.; Sham, H. L.; Collins, C. A.; Surowy, T. K.; Camp, H.
S. J. Med. Chem. 2007, 50, 3086; (c) Zhao, H.; Serby, M. D.; Smith, H. T.; Cao, N.;
Suhar, T. S.; Surowy, T. K.; Camp, H. S.; Collins, C. A.; Sham, H. L.; Liu, G. Bioorg.
Med. Chem. Lett. 2007, 17, 3388; (d) Xin, Z.; Zhao, H.; Serby, M. D.; Liu, B.; Liu,
M.; Szczepankiewicz, B. G.; Nelson, L. T. J.; Smith, H. T.; Suhar, T. S.; Janis, R. S.;
Cao, N.; Camp, H. S.; Collins, C. A.; Sham, H. L.; Surowy, T. K.; Liu, G. Bioorg. Med.
Chem. Lett. 2008, 18, 4298; Recently, a group from CV Therapeutics reported 2-
oxo-2H-quinoxalin-based SCD-1 inhibitors: (e) Koltun, D. O.; Parkhill, E. Q.;
Vasilevich, N. I.; Glushkov, A. I.; Zilbershtein, T. M.; Ivanov, A. V.; Cole, A. G.;
Henderson, I.; Zautke, N. A.; Brunn, S. A.; Mollova, N.; Leung, K.; Chisholm, J. W.;
Zablocki, J. Bioorg. Med. Chem. Lett. 2009, 19, 2048; (f) Koltun, D. O.; Vasilevich,
N. I.; Parkhill, E. Q.; Glushkov, A. I.; Zilbershtein, T. M.; Mayboroda, E. I.; Boze,
M. A.; Cole, A. G.; Henderson, I.; Zautke, N. A.; Brunn, S. A.; Chu, N.; Hao, J.;
Mollova, N.; Leung, K.; Chisholm, J. W.; Zablocki, J. Bioorg. Med. Chem. Lett. 2009,
19, 3050.
Summaries of SCD-1 inhibition, PK profilesa, and SCD-1 inhibition in mice
S
R
NH
N
O
O
OH
23
O
No.
R
IC50 (nM) Cmax
AUC (0–8 h)b t1/2
Tmax
(h)
Fb
(%) (mg/kg)
ID50
b
b
b
b
b
mouse
(
l
g/mL)
(
l
g h/mL)
8.2
10
4.9
2.0
(h)
23a 3-CF3
23c 3-CI
23e 3-OCF3
23j 3-CF3,
4-F
2
1.7
3.5
5.4
1.5
1.3
1.7
2.0
1.3
1.3
12
12
8
2
1
8
5
1
1.8
3
1.2
0.2
0.55
3
9. During the preparation of this manuscript, a group at Dainippon Sumitomo
Pharmaceutical reported 4-aminoimidazole based SCD-1 inhibitors, which
were derived from a hit compound structurally similar to 5a (Yamaguchi, H.
The 27th Medicinal Chemistry Symposium, Osaka, Japan, November, 2008).
10. All the final compounds were characterized by 1H NMR and mass spectroscopy.
11. Obushak, N. D.; Matiichuk, V. S.; Vasylyshin, R. Y.; Ostapyuk, Y. V. Russ. J. Org.
Chem. 2004, 40, 383.
12. Jeffery, T. Tetrahedron Lett. 1991, 32, 2121.
13. Halland, N. J. Am. Chem. Soc. 2004, 126, 4790.
14. (a) The aminothiazole intermediate (7a) was prepared as follows: 3-(3-
23k 3-CI,
4-F
1
3.6
14
2.1
1.0
38
2
a
A dose of each compound was either intravenously (5 mg/kg, DMA/Tween80/
saline = 10/10/80) injected into the tail vein of C57BL/6 J mice (n = 2) or orally
(20 mg/kg, 0.5% MC, n = 3) administered using an intubation tube. Plasma samples
(20 lL) were collected up to 8 h after intravenous or oral administration. The
plasma concentrations of the compounds were determined by LC/MS.
Trifluoromethylphenyl)propionaldehyde (9a). To
a
solution of 3-
b
Values are the geometric means of at least two experiments.
iodobenzotrifluoride (8a, 10.8 g) in DMF (150 mL) were added allyl alcohol
(4.1 mL), tetrabutylammonium chloride (16.6 g), sodium bicarbonate (8.34 g),
and palladium acetate (485 mg) at 0 °C. The reaction mixture was warmed to
room temperature, heated at 50 °C for 2 h, diluted with water, and extracted
with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and
concentrated. The residue was chromatographed on SiO2 (hexanes/EtOAc,
and [14C] oleate in the liver of db/db mice.18 The dose at which 50%
of the conversion is inhibited is described as ID50. The results of
this in vivo assay are summarized in Table 7 with enzymatic inhib-
itory activity and PK parameters. Most of the compounds showed
very strong potency but 23e and 23j were relatively weak in terms
of in vivo SCD-1 inhibition. It is hypothesized that the lower in vivo
activity is correlated to the lower plasma concentration and short-
er plasma half life of these compounds compared to 23a. 3-Cl Sub-
stitution on the left-hand phenyl ring, as in 23c and 23k,
demonstrated potency equal to that of 23a. 23k showed a shorter
plasma half-life but an improvement in bioavailability. 23c demon-
strated very strong enzymatic murine SCD-1 inhibition, good plas-
ma exposure, and a long plasma half-life, indicating that improved
pharmacokinetic profiles contribute to the enhancement of the
in vivo potency of these SCD-1 inhibitors.
10:1–4:1) to give 7.17 g (89%) of 9a as
a
pale yellow oil: 1H
NMR(400 MHz,CDCl3):d 9.84(1H, s), 7.49–7.39(4H, m), 3.02(2H, t, J = 7.4 Hz),
2.83(2H, t, J = 7.6 Hz).; (b) 5-(3-Trifluoromethylbenzyl)thiazol-2-ylamine (7a). To
a solution of 9a (14.0 g) in CH2Cl2 (150 mL) were added L-proline (1.6 g) and N-
chlorosuccinimide (12.1 g) at 0 °C. The reaction mixture was warmed to room
temperature, stirred for 1.5 h, and diluted with hexane (300 mL). The resulting
suspension was vigorously stirred, and filtered. The filtrate was diluted with
EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and
concentrated. The residue (17.4 g) was mixed with thiourea (5.28 g) in EtOH
(200 mL). The mixture was heated to reflux for 17 h, concentrated, diluted with
EtOAc, washed with saturated aqueous NaHCO3, and concentrated.
Chromatography of the residue on SiO2 (Chromatorex NH 100–200 mesh
FUJISILYSIA CHEMICAL LTD, CH2Cl2/EtOAC 10:1–3:1) gave 10.2 g (57%) of 7a as
a beige solid: 1H NMR (400 MHz,CDCl3): d 7.48–7.46(2H, m), 7.43–7.38(2H, m),
6.81(1H, s), 4.87(2H, br s), 4.01(2H, s); MS (ESI) m/z:259 (M+H)+.
15. (a) Compound 23a was prepared as follows: 3-(2-Hydroxyethoxy)-4-
methoxybenzoic acid methyl ester.
A
suspension of 3-hydroxy-4-
In summary, we discovered the very potent and orally bioavail-
able SCD-1 inhibitor, 3-(2-hydroxyethoxy)-4-methoxy-N-[5-(3-tri-
fluoromethylbenzyl)-thiazol-2-yl]benzamide (23a), by optimizing
the structure of the lead compound 5a, which was identified from
our in-house corporate library. Modification of the left-hand phe-
nyl of 23a resulted in the identification of robust SCD-1 inhibitors
such as 23c and 23k, which demonstrated powerful liver SCD-1
inhibition in db/db mice. Detailed pharmacology and further opti-
mization of this structural motif will be reported in the following
article.19
methoxybenzoic acid methyl ester (11, 27.8 g), 2-bromoethanol (27 mL), and
K2CO3 (42.3 g) in DMA (280 mL) was heated at 80–100 °C for 8 h. The reaction
mixture was diluted with water and extracted with EtOAc. The organic layer
was washed with brine, dried (Na2SO4), and concentrated. Chromatography of
the residue on SiO2 (hexanes/EtOAc 7:1–1:4) gave an impure product, which
was triturated in hexanes/iPr2O, collected by filtration, and dried in vacuo to
give 23.7 g (69%) of 3-(2-hydroxyethoxy)-4-methoxybenzoic acid methyl ester
as
a
pale yellow solid: MS (ESI) m/z:227 (M+H)+; (b) 4-Methoxy-3-[2-
(tetrahydropyran-2-yloxy)ethoxy]benzoic acid methyl ester: A solution of 3-(2-
hydroxyethoxy)-4-methoxybenzoic acid methyl ester (14.8 g), DHP (18 mL),
and PPTS (1.64 g) in CH2Cl2 (150 mL) was stirred at room temperature for 32 h,
concentrated, diluted with EtOAc, washed with water, saturated aqueous
NaHCO3, and brine, dried (Na2SO4), and concentrated. Chromatography of the
residue on SiO2 (hexanes/EtOAc) gave 15.1 g (74%) of 4-methoxy-3-[2-
(tetrahydropyran-2-yloxy)ethoxy]benzoic acid methyl ester as a colorless oil:
MS (FAB+) m/z:333 (M+Na)+; (c) 4-Methoxy-3-[2-(tetrahydropyran-2-
References and notes
yloxy)ethoxy]benzoic
acid
(12).
A
solution
of
4-methoxy-3-[2-
1. Dobrzyn, A.; Ntambi, J. M. Obesity Rev. 2005, 6, 169.
(tetrahydropyran-2-yloxy)ethoxy]benzoic acid methyl ester (14.4 g) in 1 N
NaOH (51 mL) and dioxane (140 mL) was heated at 70 °C. The organic solvent
was removed by evaporation. The aqueous mixture was acidified with 10%
citric acid (aq), and extracted with EtOAc. The organic layer was washed with
water and brine, dried (Na2SO4), and concentrated. Chromatography of the
residue on SiO2 (CH2Cl2/MeOH 1:0–10:1) gave an impure product, which was
vigorously stirred in hexanes/iPr2O (5:1) at 60 °C for 30 min, collected by
filtration, and dried in vacuo to give 9.24 g (67%) of 12 as a white solid: MS
(FAB+) m/z: 319 (M+Na)+; (d) 3-(2-Hydroxyethoxy)-4-methoxy-N-[5-(3-
2. Ntambi, J. M.; Miyazaki, M. Curr. Opin. Lipidol. 2003, 14, 255.
3. (a) Miyazaki, M.; Jacobsen, M. J.; Man, W. C.; Cohen, P.; Asilmaz, E.; Friedman, J.
M.; Ntambi, J. M. J. Biol. Chem. 2003, 278, 33904; (b) Wang, J.; Yu, L.; Schmidt, R.
E.; Su, C.; Huang, X.; Gould, K.; Cao, G. Biochem. Biophys. Res. Commun. 2005,
332, 735.
4. Zhang, L.; Ge, L.; Parimoo, S.; Stenn, K.; Prouty, S. M. Biochem. J. 1999, 340, 255.
5. (a) Miyazaki, M.; Kim, Y.-C.; Gray-Keller, M. P.; Attie, A. D.; Ntambi, J. M. J. Biol.
Chem. 2000, 275, 30132; (b) Flowers, M. T.; Ntambi, J. M. Curr. Opin. Lipidol.
2008, 19, 248.
6. Dobrzyn, P.; Dobrzyn, A. Drug Development Res. 2006, 67, 643.
7. Attie, A. D.; Krauss, R. M.; Gray-Keller, M. P.; Brownlie, A.; Miyazaki, M.;
Kastelein, J. J.; Lusis, A. J.; Stalenhoef, A. F. H.; Stoehr, J. P.; Hayden, M. R.;
Ntambi, J. M. J. Lipid Res. 2002, 43, 1899.
8. (a) For the typical structures of Xenon’s SCD-1 inhibitors, see: Abreo, M.;
Chafeev, M.; Chakka, N.; Chowdhury, S.; Fu, J.-M.; Gschwend, H. W.; Holladay,
M. W.; Hou, D.; Kamboj, R.; Kodumuru, V.; Li, W.; Liu, S.: Raina, V.; Sun, S.; Sun,
S.; Sviridov, S.; Tu, C.; Winther, M. D.; Zhang, Z. WO2005011655A2, February
10, 2005.; (b) Liu, G.; Lynch, J. K.; Freeman, J.; Liu, B.; Xin, Z.; Zhao, H.; Serby, M.
trifluoromethylbenzyl)thiazol-2-yl]benzamide (23a):
A
solution of 5-(3-
trifluoromethylbenzyl)thiazol-2-ylamine (7a, 4.35 g), 4-methoxy-3-[2-
(tetrahydropyran-2-yloxy)ethoxy]benzoic acid (12, 5.49 g), HATU (7.03 g),
and Et3N (4.7 mL) in DMA (90 mL) was stirred at room temperature for
4 days, and heated at 70 °C for 3 h. The reaction mixture was diluted with
EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and
concentrated. Chromatography of the residue on SiO2 (CH2Cl2/MeOH) gave
9.26 g of the amide. The amide (9.26 g) was mixed with 1 N HCl (17 mL) and
MeOH (90 mL), and heated at 50 °C for 2 h. The reaction mixture was
neutralized with 2 N NaOH, and the organic solvent was removed by