Discovery of orally active butyrolactam 11β-HSD1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2006.08.034

A series of metabolically stable butyrolactam 11β-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity, pharmacokinetic, and pharmacodynamic profiles.

Full text of DOI:10.1016/j.bmcl.2006.08.034

Bioorganic & Medicinal Chemistry Letters 16 (2006) 5555–5560
Discovery of orally active butyrolactam 11b-HSD1 inhibitors
Vince S. C. Yeh,* Ravi Kurukulasuriya, Steven Fung, Katina Monzon, William Chiou,
Jiahong Wang, Deanne Stolarik, Hovis Imade, Robin Shapiro, Victoria Knourek-Segel,
Eugene Bush, Denise Wilcox, Phong T. Nguyen, Michael Brune, Peer Jacobson
and J. T. Link
Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, AP-10-304B, Abbott Park, IL 60064, USA
Received 4 July 2006; revised 3 August 2006; accepted 7 August 2006
Available online 23 August 2006
Abstract—A series of metabolically stable butyrolactam 11b-HSD1 inhibitors have been synthesized and biologically evaluated.
These compounds exhibit excellent HSD1 potency and HSD2 selectivity, pharmacokinetic, and pharmacodynamic profiles.
Ó 2006 Elsevier Ltd. All rights reserved.
Metabolic syndrome is a cluster of factors associated
with an increased risk of atherosclerotic cardiovascular
disease and diabetes. The characteristics of the meta-
bolic syndrome include abdominal obesity, impaired
glucose tolerance, dyslipidemia, and hypertension.1
11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1)
has attracted significant attention from the pharmaceu-
tical research community as a target for the treatment of
metabolic syndrome.2 This enzyme converts the
glucocorticoid receptor (GR) inactive cortisone
(dehydrocorticosterone in rodents) into the GR active
hormone cortisol (corticosterone in rodents).3 In the
liver, cortisol stimulates gluconeogenesis through up-
regulation of the enzymes phosphoenolpyruvate car-
boxykinase and glucose 6-phosphatase, and in adipose
tissue, cortisol promotes adipogenesis and lipolysis. A
related enzyme, 11b-HSD2, catalyzes the reverse reac-
tion which, in tissues like kidney, protects the mineralo-
corticoid receptor (MR) from activation by cortisol.4
11b-HSD1 is mainly expressed in the liver, adipose,
and brain, whereas 11b-HSD2 is expressed in kidney
and other tissues where MR signaling is important.
The current hypothesis presumes a small molecule that
selectively targets 11b-HSD1 over 11b-HSD2 can be a
viable therapeutic strategy for the treatment of metabol-
ic syndrome.
Multiple structural classes of 11b-HSD1 inhibitors have
been disclosed by us5 and others.2 High-throughput
screening identified lactam 1 (Fig. 1) as a viable hit. Lac-
tam 1 has a 11b-HSD1 inhibition IC50 of 107 nM
(728 nM for mouse) and about 100-fold selectivity over
11b-HSD2 for both species.
In this communication, we describe our medicinal chem-
istry efforts based on lactam 1 and the structural evolu-
tions that took place which led us to discover a series of
butyrolactams that are orally efficacious in rodent mod-
els of metabolic syndrome.
Figure 1 shows the structure–activity relationship of our
initial analogs based on 1. The synthetic route that we
used to obtain these lactams is shown in Scheme 1.
O
O
N
Ph
N
Ph
1
4
1
2
h-HSD1 IC : 64 nM
50
h-HSD1 IC : 107 nM
50
h-HSD2 IC : > 10 uM
h-HSD2 IC : > 10 uM
50
50
O
O
HO
H NOC
2
N
Ph
N
Ph
3
4
h-HSD1 IC : 832 nM
Keywords: 11b-HSD1 inhibitors; Butyrolactams; Pharmacokinetic;
50
h-HSD1 IC : 35 nM
50
h-HSD2 IC : > 10 uM
50
Pharmacodynamic.
*
h-HSD2 IC : > 30 uM
50
Corresponding author. Tel.: +1 847 937 5567; fax: +1 847 938
1674; e-mail: vince.yeh@abbott.com
Figure 1. First-generation butyrolactam 11b-HSD1 inhibitors.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.08.034

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V. S. C. Yeh et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5555–5560
O
O
O
O
O
O
a
X
N1
N
O
N
O
N
4
5
Ph
15
16
O
O
6 = CH2
7 = CHO
O
Ar
Ar
b
R-NH2
c
R
N
Ph
h-HSD1 IC50: 85 nM
m-HSD1 IC50: 10 uM
h-HSD1 IC50: 49 nM
m-HSD1 IC50: 75 nM
8
Scheme 1. Reagents and conditions: (a) NaHMDS, THF, À78 °C,
30 min; BnBr, À78 °C to rt, 2 h, 85%; (b) i—O3, CH2Cl2, MeOH,
À78 °C, 30 min; ii—Me2S, rt, 5 h, 80%; (c) NaHB(OAc)3, THF, rt,
12 h; 60 °C, 4 h, 50–80%.
O
N
N
Ar =
CN
14
O
Alkylation of oxazolidinone imide 5 followed by ozonol-
ysis of the terminal olefin gave aldehyde 7. Tandem
reductive amination/cyclization of aldehyde 7 with vari-
ous amines gave lactam products with different N-sub-
stitutions. We found that the in vitro potency can be
significantly improved when the nitrogen of the lactam
is substituted with a large hydrophobic group such as
an adamantane, as seen in lactam 2. Based on our expe-
rience with adamantane-based inhibitors,5 unsubstituted
adamantanes are rapidly metabolized in vivo, and the
placement of a polar group such as a carboxamide on
the adamantane (e.g., lactam 4) significantly improves
metabolic stability. Lactam 4, however, lacked the desir-
able potency in our cellular 11b-HSD1 assay and accept-
able pharmacokinetic (PK) properties. Modifications on
the benzyl group did not improve the properties signifi-
cantly. In addition, most of the analogs from this struc-
tural series were much weaker in potency against the
Ar
h-HSD1 IC50: 51 nM
h-HSD2 IC50: 20 uM
m-HSD1 IC50: 62 nM
m-HSD2 IC50: 100 uM
Figure 2. In vitro potency of second-generation lactam 11b-HSD1
inhibitors. Compounds are chiral racemic mixtures.
a
O
OTBDPS
HO
OTBDPS
O
17
18
Me
Me
O
c, d
b
HO
19
OTBDPS
MeO C
O
O
MeO C
2
O
2
MeO
NH
2
21
OTBDPS
N
O
O
NH
2
20
OMe
e, f
22
MeO
N
4
HO
a
O
9
10
CO Me
2
O
N
g
O
R
Cl
23
CN
N
b, c
d
4
N
11
TBDMSO
O
O
O
24 R = CO Me
2
N
h
N
N
e, f
25 R = CONH
2
12
13
CN
TBDMSO
HO
Scheme 3. Reagents and conditions: (a) isobutyryl chloride, Et3N,
DMAP, 0 °C to rt, 5 h, 90%; (b) i—KHMDS, À78 °C, tol, 1 h;
TMSCl, À78 °C to rt, 1 h; ii—80 °C, 5 h, 90%; (c) TMS-diazomethane,
tol, MeOH, rt, 3 h; (d) O3, NaHCO3, CH2Cl2, MeOH, À78 °C, 45 min;
O
N
N
Cl
CN
˚
Me2S, À78 °C to rt, 5 h, 85%; (e) i—20, 21, 4 A MS, THF, rt, 5 h; ii—
14
NaHB(OAc)3, THF, rt, 12 h; iii—tol, 80 °C, 2 h; 85%; (f) TBAF, THF,
rt, 2 h, 92%; (g) compound 23, NaH, THF, DMPU, 0 °C to rt, 5 h,
85%; (h) i—KOTMS, THF, rt, 10 h; ii—EDCI, HOBT, i-Pr2NEt,
CH2Cl2, 2 h; NH3 in i-PrOH, 3 h, 91%.
g
O
N
CN
mouse 11b-HSD1 which precluded us from studying
these compounds in mouse models.
Scheme 2. Reagents and conditions: (a) MeOH, reflux, 5 h, 90%; (b)
LiAlH4, THF, 0 °C, 1 h, 85%; (c) TBDMSCl, imidazole, THF, rt, 99%;
(d) LiHMDS, THF, À78 °C, 30 min; MeI, 1 h, 80%; (e) LiNEt2, THF,
0 °C, 30 min; MeI, DMPU, 0 °C to rt; 4 h, 75%; (f) HCl, THF, rt, 3 h,
100%; (g) NaH, DMF, 0 °C to rt, 89%.
Faced with these drawbacks of our first-generation lac-
tam inhibitor, we decided to explore the SAR of lactams

V. S. C. Yeh et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5555–5560
Table 1. In vitro inhibition and metabolic stability data for 25–37
5557
O
R1
N
*
* = All compounds
O
are chiral racemic mixtures
R2
a
IC50 (nM)
Compound R1
R2
Microsomal stability
(% remaining)b
h-HSD1/h-HSD2 m-HSD1/m-HSD2 h-HSD1 HEK
H
H
H
N
N
28
50*/>30,000
190*/ND
260*/>100,000
250*/ND
518
NDc
EtO C
2
CN
O
29d
ND
ND
12
H N
2
N
CN
CN
H
H
H2NOC
N
30
29*/>100,000
17*/>100,000
510
H
H
H NOC
2
N
N
N
N
31
32
33
25
34
27
35
7/15,000
5/22,000
15/17,000
3/23,000
41/1,600
76/1,800
19/14,000
3/>50,000
9/100,000
10/100,000
2/10,000
39
46
88
92
CN
CN
CN
CN
H
H2NOC
H2NOC
H
500
45
91
H2NOC
H2NOC
97
N
N
N
N
32/8,000
43
ND
28
H2NOC
HO
41/14,000
14/60,000
28
N
N
N
H2N
260
67
CF
3
NH
N
N
H N
2
36
37
51/90,000
310/630
110/>100,000
430/1,600
>10,000
230
100
ND
CF3
CF3
N
N
HN
N
a Values are means of two experiments. *Kivalues.
b % remaining after a 30-min incubation with mouse liver microsome.
c ND, not determined.
d mixture of diastereomers.

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V. S. C. Yeh et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5555–5560
with substituents on position 4 of the ring. The first-gen-
eration synthesis of these lactams is shown in Scheme 2.
target enzyme in both species. Since lactam 14 is stereo-
chemically simpler than 16, the core structure of 14 was
selected for further SAR optimization.
Tandem Michael addition and cyclization between
cycloheptylamine and ester 9 gave lactam 106 which
was reduced and protected as silylether 11. Position 3
of the lactam was then sequentially alkylated, and after
removal of silyl group, a pyridyl group was appended on
the hydroxymethylene of 13 to give inhibitor 14. A brief
summary of the SAR is shown in Figure 2. Substitution
on the 4 position of lactam gave an inhibitor (15) with
good potency against the human enzyme, but no activity
for the mouse enzyme. A dramatic increase in potency
for the mouse enzyme was observed when position 3
of the lactam is alkylated with a methyl group (15 to
16). Additional a-alkylation gave lactam 14 which
showed good potency and excellent selectivity for the
An efficient synthetic route was developed to allow mod-
ifications on the nitrogen and oxygen substituents7 and a
representative synthesis is shown in Scheme 3. Acylation
of alcohol 17 with isobutyryl chloride gave ester 18. Ire-
land–Claisen rearrangement of 18 gave acid 19 which
has both the required a-gem dimethyl group, and the
b-alkoxymethylene group of the lactam core.
Acid 19 was then converted into aldehyde 20 by ester
formation followed by ozonolysis of the olefin. The lac-
tam ring was formed by a tandem reductive amination
and ring cyclization sequence between aldehyde 20 and
adamantane amine 21 which, after the removal of the
silyl-protecting group, gave lactam alcohol 22 in good
yields. The pyridyl group was attached via nucelophilic
aromatic substitution reaction between alcohol 22 and
a chloropyridine such as 23 to give 24. Final ester to
amide functional group conversion completed the
synthesis of a representative butyrolactam lactam
inhibitor 25.
O
R
N
HO
N
N
26
22
a
O
R = CO2Me
b
This reaction sequence allowed us to build lactams with
various groups on the nitrogen by reacting aldehyde 20
with a series of structurally diverse functionalized
bridged bicyclic amines5c to give inhibitors such as 31
and 33 as shown in Table 1.
R = CONH2 (27)
N
N
Scheme 4. Reagents and conditions: (a) DIAD, Ph3P, THF rt to
60 °C, 5 h, 90%; (b) i—KOTMS, THF, rt, 10 h; ii—EDCI, HOBT,
i-Pr2NEt, CH2Cl2, 2 h; NH3 in i-PrOH, 3 h, 85%.
Alcohol 22 served as a common intermediate for the
exploration of the O-aryl appendage SAR. For example,
Mitsunobu reaction between alcohol 22 and imidazole-
substituted phenol 26 gave an ester intermediate which
was converted into inhibitor 27 (Scheme 4).
Table 2. Ex vivo pharmacodynamic dataa
Compound
% inhibition in
liver 1 h/7 h/16 h
% inhibition in
fat 1 h/7 h/16 h
These compounds were tested against both human and
mouse 11b-HSD1 and 11b-HSD2 enzymes, as well as
a cell-based assay with 11b-HSD1 overexpressed in hu-
man embryonic kidney cells (HEK).5 In addition, meta-
bolic stability of these compounds was determined using
mouse liver microsomal incubation studies. The results
are summarized in Table 1.
31
25
73/33/14
99/94/67
68/30/17
NDb/71/46
a See Ref. 5b for a description of the assay.
b Not determined.
Table 3. Mouse PK dataa
Compound po nAUC (lg h/ml) CLp (L/h/kg) t1/2 (h) F (%)
Several of the compounds in Table 1 exhibited excellent
potency and selectivity for both human and mouse 11b-
HSD1. For example, lactams 25, 31, and 32 all reached
single digit nM range in terms of potency and greater
31
25
4.4
3.7
1.4
2.0
1.3
1.3
63.9
76.6
a Calculated from 5 mg/kg iv and 10 mg/kg oral po dosing.
Table 4. In vivo efficacy of compound 25, RU-486, and rosiglitazone in a 2-week DIO mouse studya
Compound
Body weightb (g)
Plasma insulinb,c (ng/ml)
Plasma glucoseb,c (mg/dL)
Plasma triglycerideb,c (mg/dL)
LFd
29.4(0.7)
41.9(0.7)
39.5(0.75)
41.6(0.7)
40.7(0.7)
0.53(0.04)
1.93(0.06)
1.5(0.25)
0.97(0.1)
1.31(0.18)
133.9(3.1)
174.0(5.8)
147.5(4.2)
143.4(4.3)
164.7(6.4)
32.8(2.6)
64.9(5.3)
43.2(3.7)
50.8(3.4)
33.3(2.5)
HFe
RU-486
rosiglitazone
25
a Lactam 25 and RU-486 were dosed at 30 mg/kg and rosiglitazone was dosed at 5 mg/kg po, bid.
b p value <0.05 by Dunnett’s test.
c Measured after 4 h fasting.
d Low-fat diet control group.
e High-fat diet control group.

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5559
than 7000-fold selectivity over 11b-HSD2. These three
inhibitors also showed excellent metabolic stability in
the microsome assay. Most of the lactams with non-ada-
mantane N-substituents (28–33) are potent inhibitors.
Lactams 30–32 are stereoisomers that differ in the orien-
tations of the substituents on the bicyclo[3.3.1]nonane
group.5c Although they are similar in their IC50 values,
compounds 30 and 31 differ dramatically in their meta-
bolic stability. The bicyclo[2.2.2]octane-substituted lac-
tam 33 is particularly interesting. This rigid bicycle has
been utilized by us in a different series of 11b-HSD1
inhibitors with good potency, selectivity, and metabolic
stability.5c In addition, it has also been incorporated in a
triazole class of inhibitors for the same enzyme with
good success.2d Lactams with non-bridged structures
such as 28 and 29 showed less potency, particularly for
the mouse enzyme. We found that the SAR of the O-aryl
portion of the molecule is quite flexible. A number of
aromatic heterocycles, or carbocycles, could be used to
obtain potent inhibitors (structures not shown) which
allowed us to fine-tune PK properties of these molecules.
Two examples (34 and 27) are shown. These lactams fea-
ture more polar aromatic substituents which can lead to
improved water solubility (calculated clogP for 27 is
2.46 vs 2.67 for lactam 25). Likewise, the polar substit-
uents on the bridged bicycle head group can also be var-
ied albeit with less flexibility. The primary caboxamide
can be replaced with a hydroxyamidine group as in 35
with good potency and stability. However, replacement
with a basic amidine group (36) abolished cellular activ-
ity and conversion to an acidic tetrazole (37) led to a loss
in selectivity.
Remarkably, plasma triglyceride levels were normalized
after treatment with this 11b-HSD1 inhibitor.
In summary, a series of potent, selective, and metaboli-
cally stable butyrolactam 11b-HSD1 inhibitors have
been identified. Based on its in vitro and pharmacoki-
netic profiles, adamantane-based lactam 25 was evaluat-
ed in DIO mice and showed efficacy in a number of
metabolic parameters.
Acknowledgment
We thank Bruce Szczepankiewicz for helpful suggestions
on the manuscript. We also thank Francis Kerdesky of
Process Chemistry Research, Abbott Labs, for provid-
ing various scale up supports.
References and notes
1. (a) Skyler, J. S. J. Med. Chem. 2004, 47, 4113; (b) Smith, S.
R. Curr. Drug Targets CNS Neurol. Disord. 2004, 3, 431.
2. For a review on patents, see: Fotsch, C.; Askew, B. C.;
Chen, J. J. Expert Opin. Ther. Pat. 2005, 3, 289; (a) Barf,
T.; Vallgarda, J.; Emond, R.; Haggstrom, C.; Kurz, G.;
Nygren, A.; Larwood, V.; Mosialou, E.; Axelsson, K.;
Olsson, R.; Engblom, L.; Edling, N.; Ronquist-Nii, Y.;
Ohman, B.; Alberts, P.; Abrahmsen, L. J. Med. Chem.
2002, 45, 3813; (b) Hermanowski-Vosatka, A.; Balkovec,
J. M.; Cheng, K.; Chen, H. Y.; Hernandez, M.; Koo, G.
C.; Grand, C. B. L.; Li, Z.; Metzger, J. M.; Mundt, S. S.;
Noonan, H.; Nunes, C. N.; Olson, S. H.; Pikounis, B.;
Ren, N.; Robertson, N.; Schaeffer, J. M.; Shah, K.;
Springer, M. S.; Strack, A. M.; Strowski, M.; Wu, K.; Wu,
T.; Xiao, J.; Zhang, B. B.; Wright, S. D.; Thieringer, R. J.
Exp. Med. 2005, 202, 517; (c) Olson, S.; Aster, S. D.;
Brown, K.; Carbin, L.; Graham, D. W.; Hermanowski-
Vosatka, A.; LeGrand, C. B.; Mundt, S. S.; Robbins, M.
A.; Schaeffer, J. M.; Slossberg, L. H.; Szymonifka, M. J.;
Thieringer, R.; Wright, S. D.; Balkovec, J. M. Bioorg.
Med. Chem. Lett. 2005, 15, 4359; (d) Gu, X.; Dragovic, J.;
Koo, G. C.; Koprak, S. L.; LeGrand, C. B.; Mundt, S. S.;
Shah, K.; Springer, M. S.; Tan, E. Y.; Thieringer, R.;
Hermanowski-Vosatka, A.; Zokian, H. J.; Balkovec, J.
M.; Waddle, S. T. Bioorg. Med. Chem. Lett. 2005, 15,
5266; (e) Xiang, J.; Ipek, M.; Suri, V.; Massefski, W.; Pan,
N.; Ge, Y.; Tam, M.; Xing, Y.; Tobin, J. F.; Xu, X.; Tam,
S. Bioorg. Med. Chem. Lett. 2005, 15, 2865; (f) Coppola,
G. M.; Kukkola, P. J.; Stanton, J. L.; Neubert, A. D.;
Marcopulos, N.; Bilci, N. A.; Wang, H.; Tomaselli, H. C.;
Tan, J.; Aicher, T. D.; Knorr, D. C.; Jeng, A. Y.; Dardik,
B.; Chatelain, R. E. J. Med. Chem. 2005, 48, 6696.
3. For recent reviews, see: (a) Draper, N.; Stewart, P. M. J.
Endocrinol. 2005, 186, 251; (b) Thieringer, R.; Herma-
nowski-Vosatka, A. Expert Rev. Cardiovasc. Ther. 2005, 3,
911; (c) Morton, N. M.; Paterson, J. M.; Masuzaki, H.;
Holmes, M. C.; Staels, B.; Fievet, C.; Walker, B. R.; Flier,
J. S.; Mullins, J. J.; Seckl, J. R. Diabetes 2004, 53, 931; (d)
Tomlinson, J. W.; Walker, E. A.; Bujalska, I. J.; Draper,
N.; Lavery, G. G.; Cooper, M. S.; Hewison, M.; Stewart,
P. M. Endocr. Rev. 2004, 25, 831.
4. (a) Krozowski, Z.; Li, K. X. Z.; Koyama, K.; Smith, R. E.;
Obeyesekere, V. R.; Stein-Oakley, A.; Sasano, H.; Coulter,
C.; Cole, T.; Sheppard, K. E. J. Steroid Biochem. Mol.
Biol. 1999, 69, 391; (b) Stewart, P. M.; Krozowski, Z. S.;
Selected compounds from Table 1 were examined in
mouse ex vivo pharmacodynamic (PD)5 and PK studies.
The results for lactams 31 and 25 are summarized in
Tables 2 and 3. For the PD experiments, the compounds
were dosed in diet-induced obese (DIO) mice at 30 mpk
and the inhibitions of 11b-HSD1 were measured ex vivo
at 1, 7, and 16 h post-dose.
Overall, both compounds exhibited good PD profiles.
The adamantane lactam 25 showed greater inhibition
of the target enzyme at later time points in both liver
and fat than the related bicyclo[3.3.1]nonane lactam
31. The mouse PK profiles of these two compounds
are very similar. Both lactams showed good systemic
exposure and oral bioavailability with acceptable clear-
ance and half-life.
Based on the favorable results shown above, lactam
25 was selected for in vivo efficacy evaluation in diet-
induced obesity (DIO) mice as a metabolic syndrome
animal model.8
Lactam 25 was dosed orally at 30 mg/kg BID for 14 days.
Several metabolic parameters were measured including
body weight, plasma insulin, plasma glucose, and plasma
triglyceride levels. RU-4869 and rosiglitazone10 were used
as positive controls. As shown in Table 4, lactam 25 in-
duced significant efficacy in weight loss and lowering of
plasma insulin levels. Blood glucose levels were also low-
ered, albeit not to the same level as the other two agents.

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Gupta, A.; Milford, D. V.; Howie, A. J.; Sheppard, M. C.;
Brunswick, NJ), for approximately 18 weeks. Three weeks
prior to the onset of compound dosing, mice were
individually housed. One week prior, mice were condi-
tioned to once daily oral gavage and vehicle (1% Tween 80
in water; Sigma Chemical, St. Louis, MO; dosing volume
4 ml/kg body weight). One day before dosing onset, 60
obese mice were assigned to five groups of 20 with equal
group mean body weights and equal variances. Com-
pounds or their vehicle (1% Tween 80 in water) was
administered daily by oral gavage (4 ml/kg) at 08:00 and
15:00 h for 28 days. A group of 20 standard diet-fed lean
mice were like vehicle dosed during the same period.
Body weight and food intake were measured on days 0, 7,
and 14.
Whorwood, C. B. Lancet 1996, 347, 88; (c) Stewart, P. M.
J. Steroid Biochem. Mol. Biol. 1999, 69, 403.
5. (a) Link, J. T.; Pliushchev, M. A.; Rohde, J. J.; Wodka,
D.; Patel, J. R.; Shuai, Q. U.S. Patent 0245534, 2005.; (b)
Yeh, V. S. C.; Patel, J. R.; Yong, H.; Kurukulasuriya, R.;
Fung, S.; Monzon, K.; Chiou, W.; Wang, J.; Stolarik, D.;
Imade, H.; Beno, D.; Jacobson, P.; Sham, H.; Link, J. T.
Bioorg. Med. Chem. Lett., in press.; (c) Yeh, V. S. C.;
Kurukulasuriya, R.; Madar, D.; Patel, J. R.; Fung, S.;
Monzon, K.; Chiou, W.; Wang, J.; Jacobson, P.; Sham, H.
L.; Link, J. T. Bioorg. Med. Chem. Lett., in press.
6. Kenda, B. M.; Matagne, A. C.; Talaga, P. E.; Pasau, P.
M.; Differding, E.; Lallemand, B. I.; Frycia, A. M.;
Moureau, F. G.; Klitgaard, H. V.; Gillard, M. R.; Fuks,
B.; Michel, P. J. Med. Chem. 2004, 47, 530.
9. (a) Garrel, D. R.; Moussali, R.; De Oliveira, A.;
Lesiege, D.; Lariviere, F. J. Clin. Endocrinol. Metab.
1995, 80, 379; (b) Friedman, J. E.; Sun, Y.; Ishizuka, T.;
Farrell, C. J.; McCormack, S. E.; Herron, L. M.;
Hakimi, P.; Lechner, P.; Yun, J. S. J. Biol. Chem. 1997,
272, 31475.
10. (a) Lehmann, J. M.; Moore, L. B.; Smith-Oliver, T. A.;
Wilkinson, W. O.; Willson, T. M.; Kliewer, S. A. J.
Biol. Chem. 1995, 270, 12953; For a review on PPAR
agonists see: (b) Henke, B. R. J. Med. Chem. 2004, 47,
4118.
7. Yeh, V. S. C.; Kurukulasuriya, R.; Kerdesky, F. Org. Lett.
2006, in press.
8. Male C57BL/6J mice (age 5–6 weeks; Jackson Labs, Bar
Harbor, ME) were housed in groups of five in polysulfone
cages in a temperature and humidity controlled facility on
a 12 h light, 12 h dark cycle (lights on at 04:00 h). Mice
had ad libitum access to water and to either a low-fat diet
(D12450B) or a high-fat content diet (D12492 containing
60% kcal from fat; both from Research Diets Inc., New