Design and synthesis of a new class of malonyl-CoA decarboxylase inhibitors with anti-obesity and anti-diabetic activities

Article abstract of DOI:10.1016/j.bmcl.2010.08.047

A new series of thiazole-substituted 1,1,1,3,3,3-hexafluoro-2-propanols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Key analogs caused dose-dependent decreases in food intake and body weight in obese mice. Acute treatment with these compounds also led to a drop in elevated blood glucose in a murine model of type II diabetes.

Full text of DOI:10.1016/j.bmcl.2010.08.047

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6088–6092
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of a new class of malonyl-CoA decarboxylase inhibitors
with anti-obesity and anti-diabetic activities
⇑
Haifeng Tang , Yan Yan, Zhe Feng, Reynalda K. de Jesus, Lihu Yang, Dorothy A. Levorse, Karen A. Owens,
Taro E. Akiyama, Raynald Bergeron, Gino A. Castriota, Thomas W. Doebber, Kenneth P. Ellsworth,
Michael E. Lassman, Cai Li, Margaret S. Wu, Bei B. Zhang, Kevin T. Chapman, Sander G. Mills, Joel P. Berger,
Alexander Pasternak
Department of Medicinal Chemistry, Metabolic Disorders, Drug Metabolism and Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of thiazole-substituted 1,1,1,3,3,3-hexafluoro-2-propanols were prepared and evaluated as
malonyl-CoA decarboxylase (MCD) inhibitors. Key analogs caused dose-dependent decreases in food
intake and body weight in obese mice. Acute treatment with these compounds also led to a drop in ele-
vated blood glucose in a murine model of type II diabetes.
Received 17 June 2010
Revised 6 August 2010
Accepted 10 August 2010
Available online 20 August 2010
Published by Elsevier Ltd.
Keywords:
Malonyl-CoA
Malonyl-CoA decarboxylase (MCD)
Acetyl-CoA
Acetyl-CoA carboxylase (ACC)
Fatty acid synthase (FAS)
Fatty acid oxidation (FAO)
Diabetes
Obesity
Glucose oxidation
Obesity has become a worldwide pandemic over the last several
decades. In the United States alone, about 33% of all adults are ob-
ese, and over 66% are regarded as overweight according to a recent
CDC survey.1 This condition is associated with increased risk of
type II diabetes, cardiovascular and cerebrovascular diseases, and
increased mortality.2 The severity of this health problem and re-
cent setbacks with several weight-loss drugs emphasize the need
for new and effective approaches to anti-obesity therapy.3
tion of feeding, presumably through increased accumulation of
malonyl-CoA, thereby demonstrating a potential role for this
metabolite in signaling satiety.7
As a potent endogenous inhibitor of carnitine palmitoyltrans-
ferase-I (CPT-I), malonyl-CoA is a key regulator of fatty acid
Lipids
Mitochondrion
ATP
It is now generally believed that a disruption of the balance be-
tween energy intake and energy expenditure is the major cause of
obesity.4 Recently, research in this area has identified the fatty acid
intermediate malonyl-CoA as a key fuel sensor in the brain.5 Mal-
onyl-CoA is synthesized by acetyl-CoA carboxylase (ACC) from
acetyl-CoA (Fig. 1). Malonyl-CoA is metabolized by fatty acid syn-
thase (FAS), which catalyzes its incorporation into long-chain fatty
acids, and by malonyl-CoA decarboxylase (MCD), which catalyzes
its decarboxylation back to acetyl-CoA. In the brain, malonyl-CoA
is involved in satiety regulation.6 Loftus et al. reported that admin-
istering the FAS inhibitor C75 to mice provoked profound inhibi-
LCFA-CoA
ACC
FAS
Acetyl-
CoA
Fatty
Acids
Malonyl-
CoA
Glucose
MCD
⇑
Corresponding author. Tel.: +1 732 5942932; fax: +1 732 5949556.
E-mail address: haifeng_tang@merck.com (H. Tang).
Figure 1. Enzymatic pathways involved in the regulation of malonyl-CoA levels and
its role in fatty acid oxidation.
0960-894X/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2010.08.047

H. Tang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6088–6092
6089
catabolism. CPT-I is the rate-limiting enzyme in fatty acid oxida-
tion (FAO) that controls long chain fatty acid transport from the
cytosol into the mitochondria. High levels of malonyl-CoA lead to
inhibition of CPT-I, which prevents FAO and favors fatty acid syn-
thesis. Conversely, low malonyl-CoA levels favor FAO by allowing
the movement of long chain fatty acids into the mitochondria.
Based on the reciprocal nature of glucose versus fatty acid oxida-
tion (Randle cycle),8 it is possible to increase cellular glucose oxi-
dation by increasing malonyl-CoA levels and thereby inhibiting
CPT-I activity. In fact, a number of clinical and experimental stud-
ies have demonstrated that small molecule MCD inhibitors can
shift energy metabolism toward glucose oxidation as an effective
approach to treating myocardial ischemia.9
Recent data support the proposition that MCD can be targeted
for the treatment of metabolic diseases. Lopaschuk and co-workers
has demonstrated that MCD knock out mice are healthy, despite
elevated malonyl-CoA levels. Importantly, these mice are resistant
to diet-induced weight gain and blood glucose elevation.9 These re-
sults indicate that it may be possible to develop therapies for obes-
ity and diabetes by increasing malonyl-CoA levels with small
molecule MCD inhibitors.
While retaining the pivotal left hand 2-aryl-1,1,1,3,3,3-hexa-
fluoro-propanol moiety, we first attempted to simplify the lead
structure by truncating the right hand portion of the molecule. To
our satisfaction, a variety of substituents can be tolerated at this
position. Compound 3, where the right hand side chain was replaced
by a simple para-toluyl group, is a fairly potent MCD inhibitor
(Scheme 1).11 Compared to 3, the 2-phenyl-1,1,1,3,3,3-hexafluoro-
propanol analog 4 is much less potent. The sulfur linkage of 3 can
be further replaced with a range of other functionalities such as
ether (5), sulfone (6), and piperazine (7). Among them, piperazine
7 emerged as a novel and versatile lead structure for small molecule
MCD inhibitors (Table 1, 7a, R = H, IC50 = 20 nM).
The synthesis of 7 is relatively straightforward. Starting from 2-
amino-thioazole 11, condensation with hexafluoroacetone hydrate
12 gave rise to 13. Subsequent treatment of 13 under Sandmeyer
conditions furnished bromide 14. If 1-aryl-piperazine 15 is com-
mercially available, the target compound can be obtained by direct
nucleophilic substitution of 15 to bromide 14. Otherwise, 7 can be
accessed by transition metal catalyzed coupling of 18 to piperazine
17, which in turn was prepared by condensation of 16 with hexa-
fluoroacetone hydrate 12 (Scheme 2).
Several classes of small molecule MCD inhibitors have been re-
ported in the literature by researchers at Chugai Pharmaceutical
Company.10 In order to develop our own small molecule MCD
inhibitors, we screened our internal compound collection, and
identified a large number of potent MCD inhibitors. Most of the
In addition to 7, related piperidine analogs 8, 9, and 10 were
also explored. Unless specified, the compounds were prepared
via the general methods described in Scheme 3. The synthesis of
1-aryl-4-[2-[5-(1,1,1,3,3,3-hexafluoro-propan-2-ol)thiazolyl]]-pipe-
ridine series 8 started with nucleophilic addition of 2-thioazole an-
ion, generated from 2-bromothioazole 19 by trans-metallation
with n-BuLi, to N-Boc-4-piperidone 20. The resulting alcoxide
was intercepted with methanesulfonyl chloride to give the mesy-
late, which upon treatment with triethylamine eliminated in situ
to give olefin 21. Olefin 21 was then reduced by hydrogenation
to afford 22, which was alkylated with hexafluoroacetone to
screen hits possess
a 1,1,1,3,3,3-hexafluoro-propanol moiety,
which is linked directly to an aromatic ring. The structures of the
two most potent hits are shown in Figure 2. In this communication,
we will outline the medicinal chemistry efforts leading to the dis-
covery of a novel class of MCD inhibitors containing the 1,1,1,3,3,3-
hexafluoro-propanol moiety.
F
CF3
O
F
O
F3C
HO
F3C
HO
F3C
S
O
O
S
F
R1
R2
N
F
F3C
HO
F3C
Ar
X
N
S
N
O
NH2
Lead Structure
1 (IC50 = 6.7 nM)
2 (IC50 = 13.3 nM)
Figure 2. MCD inhibitors identified from internal screen.
CF3
HO
F3C
F3C
HO
F3C
S
O
O
S
F3C
HO
F3C
S
S
CH3
N
N
CH3
S
N
3 (IC50 = 92 nM)
4 (IC50 = 600 nM)
S
NH2
1 (IC50 = 6.7 nM)
CF3
O
O
HO
F3C
HO
F3C
F3C
HO
F3C
S
O
S
S
S
N
F3C
N
N
N
N
CF3
5 (IC50 = 450 nM)
6 (IC50 = 5.7 nM)
7 (IC50 = 20 nM)
Scheme 1. Evolution of the lead strcuture.

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H. Tang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6088–6092
Table 1
furnish 23. Subsequent removal of the Boc group gave rise to 24.
In vitro MCD inhibition assay results for compounds 7–10
Final coupling of the aryl tail piece 18 with 24 via transition metal
catalysis led to 8. The 1-[2-[5-(1,1,1,3,3,3-hexafluoro-propan-2-
ol)thiazolyl]]-4-aryl-piperidine series 9 was prepared from nucleo-
philic substitution of 4-arylpiperidine 27 with bromide 14. The 4-
arylpiperidine 27 in turn was prepared from Negishi coupling of
zinc reagent derived from iodide 25 and aryl bromide 26, followed
by removal of the Boc group. The syntheses of 4,4-disubstituted
piperidine series 10 started from cyclization of 29 with dichloride
28. The benzyl protected piperidine was then treated under hydro-
genation conditions to furnish 30. Piperidine 30 was finally cou-
pled to bromide 14 in the presence of base, following routine
functional group manipulations, to give rise to 10.
Once prepared, all compounds were assayed in vitro for their
ability to inhibit human MCD activity.12 SAR studies of the phenyl
ring revealed that substitution with hydrophobic groups led to a
decrease in potency (Table 1, 7b–7g).13 While fluoride is tolerated,
substitution with chloride leads to a decrease in potency. Introduc-
tion of hydrogen bond acceptors did not result an increase in po-
tency, but they are generally tolerated (7l–7q). A significant
increase in potency was achieved when hydrogen bond donors
were incorporated into the phenyl ring (7r and 7s). The most po-
tent compound in this series was achieved when carboxylic acid
was introduced at the 3-position (7t). Analogs with carboxylic acid
at 2- or 4-position are significantly less potent (7u and 7v). SAR of
piperidine series 8 and 9 is largely parallel to that of 7. In general,
analogs of series 8 are less potent than those of 7; while analogs of
series 9 are slightly more potent than those of 7. The most potent
compounds were prepared from the 4,4-disubstituted piperidine
series 10. It was found that hydrogen bond donors at the 4-position
of the piperidine ring significant boost inhibition potency (10a).14
A further boost of potency was achieved when a second hydrogen
bond donor group was incorporated into the 4-phenyl ring (10h
and 10i). It is also worth noting that the aryl group can be replaced
with an alkyl group in this series, leading to potent MCD inhibitors
such as 10l and 10m (Fig. 3).
Compds
R
R0
IC50 (nM)
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
7t
7u
7v
7w
7x
7y
8a
8b
8c
8d
9a
9b
9c
9d
9e
9f
9g
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
H
20
3-CF3
3-OCF3
4-CF3
4-CH3
4-OCH3
3-OCH3
3-Cl
3-F
4-F
3,4-F
3-SO2Me
4-SO2Me
3-NO2
4-NO2
3-CN
240
320
110
59
76
46
79
8.7
8.1
11
24
44
12
8.9
16
4-CN
42
3-NH2
4-NH2
3-COOH
2-COOH
4-COOH
3-CONH2
3-(2-Tetrazole)
3-CONHCH3
H
3-F
4-F
3-CONH2
H
3-F
2-COOH
3-COOH
4-COOH
3-CONH2
3-CONHCH3
H
H
H
H
H
3.2
2.7
1.3
5.1
19
2.2
1.6
2.3
37
36
19
14
13
11
1.7
0.9
4.0
1.8
3.1
4.5
11
1.1
4.9
4.7
1.4
1.6
0.5
0.6
0.9
3.3
OH
CN
COOH
CONH2
CONHCH3
COOH
2-Tetrazole
CONH2
COOH
CONHSO2CH3
CONHCH2CF3
Based on their enzyme inhibitory potency and structural diver-
sity, a selected set of compounds were further evaluated in a db/db
mouse hepatocyte whole cell assay (Table 2).15 In contrast to their
high potency in the in vitro assay, these compounds were much
less active in the whole cell assay. In general, polar functional
groups such as carboxylic acid and carboxamide are essential for
whole cell activity. Without polar groups, the compounds are
4-F
2-F
3-COOH
3-COOH
H
H
CF3
CF3
HO
F3C
HO
O
3 H2O
CF3
R
S
N
a
b
S
N
S
N
HN
N
F3C
NH2
Br
F3C
NH2
11
12
CF3
13
14
15
HO
c
S
N
R
F3C
N
N
7
CF3
CF3
HO
F3C
HO
F3C
S
N
O
R
d
S
N
R
3 H2O
CF3
e
S
N
N
NH
X
N
N
N
NH
F3C
16
12
17
18 (X = Br, I)
7
0
0
Scheme 2. Reagents and conditions: (a) 4 ÅA molecular sieves, toluene, 120 °C, 2 h, 89%; (b) NaNO2, CuBr, water, 48% HBr, 65%; (c) Et3N, DMSO, 100 °C, 20–90%; (d) 4 ÅA
molecular sieves, toluene, 120 °C, 2 h, 60%; (e) Pd(OAc)2, X-Phos, NaOt-Bu, toluene, 100 °C, 10–80%.

H. Tang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6088–6092
6091
CF3
HO
S
N
S
N
S
S
a
c
b
F3C
N
Boc
N
Boc
e
N
Boc
Br
O
N Boc
N
N
19
20
CF3
21
22
8
23
CF3
HO
HO
F3C
R
S
N
R
S
N
d
F3C
X
N
NH
24
18 (X = Br, I)
CF3
CF3
HO
HO
R
S
N
R
R
f, g
h
S
F3C
F3C
Br
HN
N
Boc
N
I
Br
N
25
26
27
14
9
CF3
Cl
Cl
R
CF3
R
R
HO
HO
F3C
i, j
S
N
k
S
N
F3C
Bn
N
HN
N
Br
R'
R'
R'
29
28
30
14
10
Scheme 3. Reagents and conditions: (a) n-BuLi, THF, ꢀ78 °C, 1 h, 1.2 equiv MsCl, 2.0 equiv Et3N, 0 °C, 60%; (b) H2, 10% Pd/C, MeOH, 95%; (c) LDA, THF, CF3COCF3, ꢀ78 °C, 75%,
(d) TFA, 25 °C, 2 h, 98%; (e) 10 mol % Pd(OAc)2, 15 mol % X-Phos, NaOt-Bu, toluene, 100 °C, 20–60%; (f) Zn powder, 5 mol % Pd(dppf)Cl2, 10 mol % CuI, DMA, 85 °C, 50–90%, (g)
TFA, 25 °C, 2 h, 98%; (h) Et3N, DMSO, 100 °C, 20–90%; (i) 3.0 equiv NaH, THF, 80 °C, 20–80%; (j) Pd/C, H2, EtOH, 95%; (k) Et3N, DMSO, 100 °C, 20–90%.
Table 2
CF3
CF3
HO
HO
Hepatocyte whole cell assay for selected compounds 7–
S
N
S
N
10
F3C
F3C
N
N
a
OH
OH
Compds
IC50 (nM)
EC50 (nM)
O
O
7k
7w
7y
8c
8d
9d
9f
10d
10e
10h
10j
11.4
2.2
2.3
19
13.8
0.9
1.8
4.9
4.7
0.5
0.9
>20,000
1400
630
>20,000
2000
230
950
1100
640
10l (IC50 = 0.4 nM)
10m (IC50 = 3.4 nM)
Figure 3. 4-Alkyl substituted piperidine analogs 10l and 10m.
generally inactive ( 7k, 8c >20,000 nM). However, polar groups
usually lead to undesirable pharmacokinetics and brain penetra-
tion (PK/BP) properties. Since energy balance is regulated by the
hypothalamus, adequate brain penetration is believe to be crucial
for compounds to demonstrate efficacy in proof of concept studies.
Gratifyingly, we were able to improve PK/BP properties while
maintaining whole cell potency by converting the primary carbox-
amide (7w) into the corresponding secondary carboxamide (7y).16
It is also worth noting that the 4,4-disubstituted series 10 was
shown to have better PK/BP properties than the other series.
Compound 10d has good PK/BP properties despite the primary
carboxamide group.17
150
500
a
n = 3.
Table 3
Results from the chronic FI/BW studies with C57B6N mice
Compds (dosage
at mpk/day)
Body weight
change (%)
Total caloric
intake (%)
Hypothalamic
malonyl-CoA
change (%)
Based on their superior hepatocyte assay potency and desirable
PK/BP properties, compounds 7y and 10d were scaled up for a
14-day chronic efficacy studies in obese C57B6N mice; 7w, a less
brain penetrant compound, was synthesized to serve as a negative
control. The inhibitors were dosed at 30 and 100 mpk/day po for
2 weeks. At the end of the studies, hypothalami were collected
for quantitative malonyl-CoA analysis.18 The two brain penetrant
compounds, 7y and 10d reduced food intake (FI) and body weight
(BW) at 100 mpk, while no significant effect was observed with
7w. These results correlated well with hypothalamic malonyl-
CoA levels (Table 3). Mice treated with the brain penetrant com-
pound 7y showed a dose-dependent response; 30 and 100 mpk
treatments resulted in 65% and 186% increases in hypothalamic
malonyl-CoA levels, respectively, versus the vehicle control. The
other brain penetrant compound, 10d provided a 70% increase in
7w (30)
7w (100)
7y (30)
7y (100)
10d (30)
10d (100)
ꢀ3.3
ꢀ2.2
0.8
0.8
ꢀ1.3
ꢀ12.4a
ꢀ2.4
ꢀ5.7
50
36
ꢀ2.1
65a
186b
29
ꢀ20.0a
ꢀ5.5
ꢀ14.3a
70b
C57B6N mice maintained on D12492 for 16 weeks, n = 9 per group.
% Normalized versus control.
a
p <0.05.
p <0.01.
b
malonyl-CoA at 100 mpk treatment, but no significant elevation
at 30 mpk treatment. No significant increase of hypothalamic mal-
onyl-CoA levels was obtained with the less brain penetrant com-
pound, 7w.

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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.
6. Lam, T. K. T.; Schwartz, G. J.; Rossetti, L. Nat. Neurosci. 2005, 8, 579.
7. Loftus, T. M.; Jaworsky, D. E.; Frehywot, G. L.; Townsend, C. A.; Ronnett, G. V.;
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.;
Harmon, C.; Bar, R.; Dyck, J. R. B.; Lopaschuk, G. D.; Nazdan, A. M. J. Med. Chem.
2006, 49, 1517; (c) Cheng, J.; Mak, C. C.; Huang, Y.; Penuliar, R.; Nishimoto, M.;
Zhang, L.; Chen, M.; Wallace, D.; Arrhenius, T.; Chu, D.; Yang, G.; Barbosa, M.;
Bar, R.; Dyck, J. R. B.; Lopaschuk, G. D.; Nazdan, A. M. Bioorg. Med. Chem. Lett.
2006, 16, 3484; (d) Cheng, J.; Huang, Y.; Penuliar, R.; Nishimoto, M.; Liu, L.;
Arrhenius, T.; Yang, G.; O’leary, E.; Barbosa, M.; Barr, R.; Dyck, J. R. B.;
Lopaschuk, G. D.; Nadzan, A. M. J. Med. Chem. 2006, 49, 4055; (e) Wallace, D. M.;
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2007, 17, 1127.
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.;
Roberts, R.; Geltman, E. M.; Sobel, B. E. Am. Heart J. 1984, 108, 31; (c) Kannel, W.
B.; McGee, D. L. Circulation 1979, 59, 8.