6092
H. Tang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6088–6092
3. For problems associated with Phen-Fen, see: CDC-MMWR, 1997, 46, 1061; also
Table 4
see: (a) Rothman, R. B.; Ayestas, M. A.; Dersch, C. M.; Baurmann, M. H.
Circulation 1999, 100, 869; For problems associated with Rimonabant, see: (b)
Christensen, R.; Kristensen, P. K.; Bartels, E. M.; Bliddal, H.; Astrup, A. Lancet
2007, 370, 1706.
Results from the acute glycolysis assay with db/db mice
Compds
Dosage (mpk)
Blood glucose
correction (%)
b-HBA
decrease (%)
4. Pocai, A.; Lam, T. K. T.; Obici, S.; Gutierrez-Juarez, R.; Muse, E. D.; Arduini, A.;
Rossetti, L. J. Clin. Invest. 2006, 111, 1.
5. Folmes, C. D. L.; Lopaschuk, G. D. Cardio. Res. 2007, 73, 278.
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Lane, M. D.; Kuhajda, F. P. Science 2000, 288, 2379.
7w
7y
10d
10j
10j
10j
30
30
30
3
10
30
32a
30a
41a
28
78b
65b
60b
ꢀ12
53b
60b
53b
48a
8. Randle, P. J. Diabetes Metab. Rev. 1998, 14, 263.
9. Dyck, J. R. B.; Hopkins, T. A.; Bonnet, S.; Michelakis, E. D.; Young, M. E.;
Watanabe, M.; Kawase, Y.; Jishage, K.; Lopaschuk, G. D. Circulation 2006, 114,
1721.
Db/db mice 11 weeks old, n = 5.
a
p <0.05.
p <0.005.
b
10. (a) Cheng, J.; Chen, M.; Liu, B.; Hou, Z.; Arrhenius, T.; Nazdan, A. M. Bioorg. Med.
Chem. Lett. 2006, 16, 695; (b) Cheng, J.; Chen, M.; Wallace, D.; Tith, S.;
Haramura, M.; Liu, B.; Mak, C. C.; Arrhenius, T.; Reily, S.; Brown, S.; Thorn, V.;
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11. SAR study of 3 on the phenyl ring led to significant improvement in enzyme
inhibition potency. These results will be reported in a separate communication.
12. Truncated human MCD was used in the assay. A set of 12 compounds were
assayed with the truncated human MCD and the full length human MCD. The
IC50 values were within twofolds of each other. For detailed assay protocols,
please see: Dyck, J. R. B.; Berthiaume, L. G.; Thomas, P. D.; Kantor, P. F.; Barr, A.
J.; Barr, R.; Singh, D.; Hopkins, T. A.; Voilley, N.; Prentki, M.; Lopaschuk, G. D.
Biochem. J. 2000, 350, 599–608.
In order to explore the hypothesis that small molecule MCD
inhibitors can serve as therapy for type II diabetes, the acute met-
abolic effects of four compounds were studied in a diabetic db/db
mice model.19 Blood glucose levels were determined at the end of
the study. In addition, the circulating levels of b-hydroxybutyrate
(b-HBA), a ketone emanating from fatty acid oxidation (FAO) in
the liver, were also measured at the termination of the study as a
biomarker of hepatic FAO activity. To our delight, mice treated
with MCD inhibitors displayed decreased b-HBA levels, and most
importantly, significant reductions in their elevated blood glucose
levels (Table 4).
In conclusion, we have discovered a new class of potent small
molecule MCD inhibitors. SAR studies led us to the synthesize a
number of brain penetrant compounds with good PK profiles. Sub-
sequently, we used these inhibitors to demonstrate that raising
malonyl-CoA in the hypothalamus is associated with a reduction
in body weight and food intake, thus validating MCD as a viable
target for the treatment of obesity. Moreover, administration of
these compounds to diabetic db/db mice ameliorated hyperglyce-
mia by apparently shifting catabolic nutrient metabolism from
fatty acid to glucose oxidation, thereby establishing MCD as a po-
tential therapy for type II diabetes.
13. Analogs substituted with other aromatic rings were also synthesized, but are
generally less potent than their phenyl analogs.
14. Compound 10a was prepared from direct nucleophilic substitution of
commercially available 4-hydroxy-4-phenylpiperidine to bromide 14.
15. Compounds of interest were incubated with primary db/db mouse hepatocytes
for 30 min. Malonyl-CoA levels were then measured to assess their ability to
inhibit whole cell MCD activity.
16. Plasma/brain drug levels at 30 mpk 4 h after po dosing in mice: 7w plasma
2.38
17. Plasma/brain drug levels for 10d at 30 mpk 4 h after po dosing in mice: plasma
15.8 M, brain 5.4 M.
lM, brain 0.08 lM; 7y plasma 20.5 lM, brain 0.79 lM.
l
l
18. The levels of malonyl-CoA in the collected hypothalami were quantified by
HPLC with known internal standard.
19. Assay protocol: db/db mice were orally dosed with compounds or vehicle in
0.5% methylcellulose 5 h after food was removed. Two hours later blood
samples were obtained by the tail vein. Plasma glucose and b-HBA levels of
mice dosed with compounds and vehicle were assayed. Percent correction of
glucose and percent decrease in b-HBA of the compounds were calculated
versus vehicle control.
References and notes
1. CDC, 2003-2004 National Health and Nutrition Examination Survey (NHANES).
2. (a) Finer, N. Clin. Med. 2003, 3, 23; (b) Jaffe, A. S.; Spadaro, J. J.; Schechtman, K.;
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B.; McGee, D. L. Circulation 1979, 59, 8.