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References and notes
Plasma triglyceride concentration
400
300
200
100
0
1. Dobrzyn, A.; Ntambi, J. M. Obes. Rev. 2005, 6, 169.
2. Ntambi, J. M.; Miyazaki, M. Curr. Opin. Lipidol. 2003, 14, 255.
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M.; Ntambi, J. M. J. Biol. Chem. 2003, 278, 33904; (b) Wang, J.; Yu, L.; Schmidt, R.
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*
Control
3 mg/kg
10 mg/kg
30 mg/kg
Compd 24
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.
Figure 2. Plasma triglyceride reduction in Zucker fatty rats (n = 4, tested for
significance in paired t-test,) after administration of 24 for 7 days (qd). *P = 0.012
versus control.
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, Feb 10,
2005.; (b) For the typical structures of Merck Frosst’s SCD-1 inhibitors, see:
Black, C.; Deschenes, D.; Gagnon, M.; Lachance, N.; Leblanc, Y.; Leger, S.; Li, C.
S.; Oballa, R. M. WO2007009236A1, Jan 25, 2007; (c) Dobrzyn, A.; Dobrzyn, P.
Exp. Opin. Ther. Pat. 2008, 18, 457; (d) Li, G. Exp. Opin. Ther. Pat. 2009, 19, 885;
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A.; Sham, H. L.; Collins, C. A.; Surowy, T. K.; Camp, H. S. J. Med. Chem. 2007, 50,
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Camp, H. S.; Collins, C. A.; Sham, H. L.; Liu, G. Bioorg. Med. Chem. Lett. 2007, 17,
3388; (h) 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;
(i) 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; (j) 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; (k) Koltun, D. O.;
Zilbershtein, T. M.; Migulin, V. A.; Vasilevich, N. I.; Parkhill, E. Q.; Glushkov, A.
I.; McGregor, M. J.; Brunn, S. A.; Chu, N.; Hao, J.; Mollova, N.; Leung, K.;
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applications describing SCD-1 inhibitors have recently been reviewed: Liu, G.
Expert. Opin. Ther. Pat. 2009, 19, 1169.
(c Log P = 1.1) that resulted in better solubility at neutral pH and
metabolic stability. With significant improvement in ADME pro-
files, 24 demonstrated a higher plasma concentration (Cmax and
AUC) and better bioavailability than those of 19b in C57BL/6J mice
after oral administration. It is fairly assumed that the favorable PK
profiles of 24 led to a very strong inhibitory activity against liver
SCD-1 in db/db mice.
For multiple dosing studies of SCD-1 inhibitors, 24 was tested in
a 7-day efficacy study using Zucker fatty rats.13 It is known that
Zucker fatty rats incorporate a mutation in the leptin receptor that
results in a 10-fold reduction in the binding affinity for leptin and
significantly attenuated leptin signal.16 The phenotype of the Zuc-
ker fatty rats includes components of Metabolic Syndrome such as
obesity, insulin resistance and a dyslipidemia (e.g., hypertriglycer-
idemia and hypercholesterolemia).17 After once-daily administra-
tion for 7 days, 24 dose-dependently reduced the plasma
triglyceride levels (Fig. 2), with a 56% reduction at 30 mg/kg
(*P = 0.012 vs control). In addition, a 15% reduction (no statistical
significance) in body weight gained was observed at 30 mg/kg,
while there were only marginal changes in the plasma glucose
and insulin levels. In the preliminary analysis, we did not observe
severe abnormalities in the skin or eyes of the Zucker fatty rats at
30 mg/kg (cutaneous abnormalities and narrow eye fissure have
been reported in studies on SCD-1 deficient mice18). We assume
that the balanced combination of the strong potency and short
plasma half life of 24 resulted in pharmacological efficacy in vivo
and may be beneficial in preventing adverse events. Currently,
we do not know the long term effect of 24 on Zucker fatty rats.
However, some abnormalities18 may be observable with an ex-
tended administration period. More detailed pharmacological
studies of the 6-(4-benzoylpiperidin-1-yl)pyridazine-3-carboxam-
ide-based SCD-1 inhibitors will be reported elsewhere.
In summary, we discovered a very potent and orally bioavailable
SCD-1 inhibitor, 6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-
3-carboxylic acid (2-hydroxy-2-pyridin-3-ylethyl)amide (24), by
optimizing the structure of the piperazine-based SCD-1 inhibitor
(1) that was reported in Xenon’s patent. Structurally, the 2-Me
substituted benzoylpiperidine on the left and 3-pyridyl on the right
were the key elements to generate favorable PK profiles and in vivo
potency. Further optimization of 24 and related compounds, espe-
cially structural modification of the 2-alkyl substituted benzoylpi-
peridine to develop novel ring structures, is currently in progress.
Part of this effort will be reported in due course.
9. (a) Uto, Y.; Ogata, T.; Harada, J.; Kiyotsuka, Y.; Ueno, Y.; Miyazawa, Y.; Kurata,
H.; Deguchi, T.; Watanabe, N.; Takagi, T.; Wakimoto, S.; Okuyama, R.; Abe, M.;
Kurikawa, N.; Kawamura, S.; Yamato, M.; Ohsumi, J. Bioorg. Med. Chem. Lett.
2009, 19, 4151; (b) Uto, Y.; Ogata, T.; Kiyotsuka, Y.; Miyazawa, Y.; Ueno, Y.;
Kurata, H.; Deguchi, T.; Yamada, M.; Watanabe, N.; Takagi, T.; Wakimoto, S.;
Okuyama, R.; Konishi, M.; Kurikawa, N.; Kono, K.; Ohsumi, J. Bioorg. Med. Chem.
Lett. 2009, 19, 4159.
10. While other isoforms of SCD are known to exist in mouse liver, the assay
protocol in the supplemental information is considered to evaluate the
inhibitory activity against SCD-1 because the expression levels of the other
SCD isoforms are low.
11. Benzoylpiperidine-based SCD-1 inhibitors were previously exemplified in the
following patents: (a) Kamboj, R.; Zhang, Z; Fu, J-M.; Sviridov, S.; Sun, S.; Seid,
B. M.; Raina, V.; Hou, D.; Chowdhury, S.; Liu, S.; Kodumuru, V.; Chakka, N.
WO2006034338A1, Mar 30, 2006. (b) Uto, Y.; Kiyotsuka, Y.; Kurata, H.; Ogata,
T.; Okuyama, R.; Konishi, M.; Kurikawa, N.; Ohsumi, J. JP200919013, Jan 29,
2009.
12. All the final compounds were characterized by 1H NMR and mass spectroscopy.
13. For the experimental procedures, please see Supplementary data.
14. Leazer, J. L., Jr.; Cvetovich, R.; Tsay, F-R.; Dolling, U.; Vickery, T.; Bachert, D. J.
Org. Chem. 2003, 68, 3695. and references are therein.
15. Abarbri, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett. 1999, 40, 7449.
16. Chua, S. C., Jr.; White, D. W.; Wu-Peng, X. S.; Liu, S. M.; Okada, N.; Kershaw, E.
E.; Chung, W. K.; Power-Kehoe, L.; Chua, M.; Tartaglia, L. A.; Leibel, R. L.
Diabetes 1996, 45, 1141.
17. Amy, R. M.; Dolphin, P. J.; Pederson, R. A.; Russell, J. C. Atherosclerosis 1988, 69,
199.
18. (a) Miyazaki, M.; Man, W. C.; Ntambi, J. M. J. Nutr. 2001, 131, 2260; (b) Binczek,
E.; Jenke, B.; Holtz, B.; Gunter, R. H.; Thevis, M.; Stoffel, W. Biol. Chem. 2007,
388, 405.
Supplementary data
Supplementary data associated with this article can be found, in