Discovery of azetidinone acids as conformationally-constrained dual PPARα/γ agonists

Article abstract of DOI:10.1016/j.bmcl.2008.01.126

A novel class of azetidinone acid-derived dual PPARα/γ agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARα and PPARγ receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.

Full text of DOI:10.1016/j.bmcl.2008.01.126

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 1939–1944
Discovery of azetidinone acids as conformationally-constrained
dual PPARa/c agonists
Wei Wang,*,a Pratik Devasthale,a,* Dennis Farrelly,b Liqun Gu,b Thomas Harrity,b
Michael Cap,b Cuixia Chu,b Lori Kunselman,b Nathan Morgan,b Randy Ponticiello,b
Rachel Zebo,b Litao Zhang,c Kenneth Locke,c Jonathan Lippy,c Kevin O’Malley,c
Vinayak Hosagrahara,d Lisa Zhang,d Pathanjali Kadiyala,e Chiehying Chang,f
Jodi Muckelbauer,f Arthur M. Doweyko,g Robert Zahler,a Denis Ryono,a
Narayanan Hariharanb and Peter T. W. Chenga
aMetabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA
bMetabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA
cLead Evaluation, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA
dMetabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA
eBio-Analytical Services, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA
fMacromolecular Crystallography, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA
gComputer-Assisted Drug Design, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA
Received 16 October 2007; revised 30 January 2008; accepted 31 January 2008
Available online 7 February 2008
Abstract—A novel class of azetidinone acid-derived dual PPARa/c agonists has been synthesized for the treatment of diabetes and
dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARa and
PPARc receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A
high-yielding method for N-arylation of azetidinone esters is also described.
Ó 2008 Elsevier Ltd. All rights reserved.
For the past decade, peroxisome proliferator-activated
receptors (PPARs), which are members of a nuclear hor-
mone receptor super-family, have attracted much atten-
tion as novel therapeutic targets for the treatment of
diabetes and dyslipidemia.1 The PPARa receptor,
mainly expressed in the liver, alters genes involved in
fatty acid oxidation and lipid metabolism. On the other
hand, the PPARc receptor is predominantly expressed
in the adipose tissue and macrophages and affects genes
involved in lipid synthesis and storage pathways. Activa-
tion of PPARc promotes pre-adipocyte differentiation
and improves insulin sensitivity. PPARa ligands (e.g.,
fenofibrate and gemfibrozil) and PPARc ligands (e.g.,
rosiglitazone and pioglitazone) have been in clinical use
for the treatment of dyslipidemia and diabetes, respec-
tively. A considerable amount of effort has thus been ex-
pended in the development of dual PPARa/c agonists for
the treatment of diabetes as well as the associated dysli-
pidemia. Muraglitazar,2 tesaglitazar,3 KRP-297 (MK-
767)4, and TAK-5595 are examples of late stage dual
PPARa/c clinical candidates which have demonstrated
efficacy in glucose normalization and correction of lipid
abnormalities in diabetic patients. However, the develop-
ment of all of these advanced clinical candidates has been
discontinued for multiple reasons.6 Therefore, the dis-
covery of a safe and efficacious dual PPARa/c agonists
is still an important goal.
We have previously reported on the discovery of our
first dual PPARa/c agonist clinical candidate, muraglit-
azar (1, from the oxybenzylglycine chemotype), detailing
its in vitro, in vivo (rodent and human), pharmacoki-
netic, and toxicological profiles as well as some prelimin-
ary SAR.7 Subsequently, our goal was to identify
Keywords: PPAR; Dual PPARa/c agonists; Antidiabetic azetidinones;
Boronic acid coupling; Conformational constraint.
*
Corresponding author. Tel.:+1 609 818 4974; fax:+1 609 818 3460
(P.D.); e-mail: pratik.devasthale@bms.com
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.01.126

1940
W. Wang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1939–1944
chemotypes that would be significantly structurally dis-
tinct from muraglitazar in order to minimize the risk
of any potential unanticipated structure-based liabilities
associated with the alkoxybenzylglycines.
O
O
H3CO
N
2
a-d
9
Cl
OH
HO
BnO
f
e
meta: 7
para: 8
meta: 5
para: 6
Here we disclose a novel class of conformationally-con-
strained azetidinone analogs of 1. Conceptually,
constraining the glycine carbamate moiety of 1 into a
4-membered ring followed by an O ! N transposition
yielded azetidinones 2 (Fig. 1). The azetidinone core
(2) can be envisioned to be generated from ketene (3)
and imine (4) via the well-documented Staudinger reac-
tion.8 The synthesis of Prostate Specific Antigen inhibi-
tors based on structurally similar azetidinone cores has
previously been reported.9
O
N
OH
HO
H
N
BnO
O
O
OCH 3
OCH3
meta: 12
para: 13
meta: 10
para: 11
O
OMs
14
N
O
OH
Ph
O
N
Ph
N
O
O
g-i
OCH3
j
(-)-17 and (+)-18
(-)-19 and (+)-20
meta:15
para:16
Our first synthesis of the 3- and 4-alkoxy substituted
azetidinone analogs starting from either 3-(hydroxy-
phenyl)propanoic acid (5) or 4-(hydroxyphenyl)propa-
noic acid (6) is described in Scheme 1. The carboxylic
acids 5 and 6 were converted to the known acid chlo-
rides 7 and 8,9 which were purified by vacuum distilla-
tion. Using the Staudinger conditions described by
Adlington and co-workers,9 acid chlorides 7/8 were
readily coupled with diimine 9 to provide the corre-
sponding. b-lactams which, after acid hydrolysis, yielded
the 3- and 4-substituted azetidinone aldehydes 10 and 11
as single cis diastereomers. Concomitant debenzylation
and aldehyde reduction of 10 and 11 to the correspond-
ing alcohols were carried out using H2 and 10% Pd-C.
Alkylation of the resulting phenols with mesylate 142
and stepwise oxidation of the primary alcohol to the
corresponding carboxylic acids afforded the racemic aze-
tidinone acids 15 and 16. The racemates 15 and 16 were
separated by chiral HPLC to provide the individual
enantiomers (17, 18, 19, 20). An X-ray co-crystal of
the faster-moving isomer (17) of racemate 15 [on Chiral-
cel OD column (70% Heptane/IPA + 0.1% TFA)] with
PPARa receptor ligand binding domain (LBD) at
k
Scheme 1. Reagents and conditions: (a) cat. H2SO4, MeOH, 25 °C,
overnight, >98%; (b) benzyl bromide, K2CO3, CH3CN, reflux, 2 h,
>95%; (c) LiOHÆH2O, THF–H2O (1:1), 25 °C, 16 h; (d) oxalyl chloride,
CH2Cl2, 0–25 °C followed by fractional distillation, 80%; (e) 9, Et3N,
toluene, 40 °C; aqueous HCl, 40–80%; (f) H2 (60 psi), 10% Pd/C, 91%;
(g) 14, K2CO3, CH3CN, reflux, 60%; (h) Dess–Martin periodinane,
CH2Cl2; (i) Jones reagent, acetone, 31% for two steps; (j) chiral HPLC
separation (Chiralcel OD column, 70% Heptane/IPA + 0.1% TFA); (k)
chiral HPLC separation (Chiralcel AD column, 65% Heptane/
IPA + 0.1% TFA).
10
˚
2.35 A resolution was obtained (Fig. 2). The absolute
stereochemistry of compound 17 was thus determined
to be 3S,4S.
To simultaneously explore the SAR of the N-aryl region
as well as to accommodate the variation of the aryloxaz-
ole moiety, we were able to modify this flexible synthetic
Figure 2. X-ray crystallographic analysis of 17 bound to PPARa at
˚
2.35 A (only ligand shown).
route in order to allow for the introduction of the N-aryl
group at a later stage (Scheme 2). Thus, the 3- or 4-
substituted azetidinone aldehydes 10 and 11 were oxi-
dized to the corresponding carboxylic acids, which were
protected as their methyl (21a,22a) or tert-butyl (21b)
esters. The N-4-methoxyphenyl group was removed by
ceric ammonium nitrate to give the key N-unsubstituted
lactams (23a, 23b, 24a). There is only one report of an
efficient method for the N-arylation of 2-azetidinones,
viz., through the use of aryl bromides in the presence
of Pd catalysts.11 Another method, which involves the
use of aryl stannanes, is known to give poor yields with
2-azetidinones.12 To our knowledge, there are no reports
of direct couplings of 2-azetidinones with boronic acids
in the literature.
O OH
1. Conformational
O
N
N
O O
constraint
O
2. Hetero atom
transposition
Muraglitazar 1
OMe
O
"2+2"
OH
Cycloaddition
R'
Ar
4
RO
N
+
RO
O
N
R
O
Azetidinones 2
3
Figure 1. Design of azetidinone acids as conformationally-constrained
analogs of muraglitazar.

W. Wang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1939–1944
Table 1. Copper-mediated N-arylation of azetidinone 23aa
1941
O
O
a,b
OR
H
O
BnO
BnO
N
N
O
O
O
ArB(OH)2
O
BnO
BnO
OCH3
OCH3
OCH3
OCH3
N
Cu(OAc)2/DCE
TEA/Py/4Å sieves
NH
O
Ar
meta: 21a & 21b
para: 22a
O
meta: 10
para: 11
23
Compound
4
O
N
Yieldsb (%)
O
OR
NH
Ar
e
OR
Ar
c
BnO
BnO
34a
34b
34c
34d
34e
34f
4-Fluorophenyl
4-Chlorophenyl
96
99
96
96
97
93
O
4-Phenoxyphenyl
4-tert-Butylphentyl
3-Trifluomethylphenyl
6-Methoxypyridin-3-yl
meta: 23a
meta: 23b
para: 24a
meta: 25a & 25b
para: 26a
d
(+)-23band (-)-23b
OMs
N
O
O
R1
29
a For a typical procedure, see Ref. 13.
b Isolated yields after flash chromatography.
f
OR
Ar
HO
N
O
g
meta: 27a & 27b
para: 28a
O
in Scheme 1. The individual azetidinone enantiomers
(+)-23b (3S,4S) and (ꢀ)-23b(3R,4R) were obtained from
racemic intermediate 23b by chiral HPLC separation.
Each enantiomer was then converted to the target acid
in the usual manner. The assignment of stereochemistry
of (+)-23b and (ꢀ)-23b was based on the conversion of
(+)-23b to (ꢀ)-17.
h
OR
O
N
O
N
Ar
O
R1
meta: 30a & 30b
para: 31a
O
a: R = CH3
b: R = t-Bu
OH
O
N
O
N
Ar
O
R1
To assess the absolute stereochemical preference of the
substituents on the azetidinone, individual enantiomers
17 and 18 were tested in PPARa and PPARc in vitro as-
says. Binding and functional data on both receptors
indicated that the 3S,4S stereochemistry was optimal
for PPARa/c activity (Table 2). This stereopreference
was consistent with our modeling, which predicted that
the 3- and the 4-alkoxybenzyl azetidinone analogs with
the 3S,4S stereochemistry would be more active. There-
fore, by analogy to 17 and 18, the 3S,4S stereochemistry
was assigned to the more active enantiomers of the pairs
19/20, 35/36, and 37/38 (see Table 3).
meta: 32
para: 33
Scheme 2. Reagents and conditions: (a) Jones reagent, acetone, 1 h,
>98%; (b) 21a and 22a (R = CH3): TMSCHN2, CH3OH, 1 h, 62% for
two steps; 21b (R = tert-butyl): tert-butyl 2,2,2-trichloroacetimidate,
BF3ÆOEt2, cyclohexane, CH2Cl2, 6 h, 64%; (c) cerium ammonium
nitrate, CH3CN–H2O, 8 h, 75–82%; (d) chiral HPLC separation
(Chiralcel AD column, 92–77% Heptane/IPA + 0.1% TFA); (e)
ArB(OH)2, Cu(OAc)2, Et3N, pyridine, CH2Cl2 or DCE, 25 °C, 5 h,
90–99%; (f) H2 (1 atm), 10% Pd on active carbon, 61–86%; (g) 29,
K2CO3, CH3CN, reflux, 55–81%; (h) for R = CH3: LiOHÆH2O, THF–
H2O (1:1), 25 °C, 16 h, 20–50%; R = tert-butyl: TFA, CH2Cl2, 2 h, 61–
72%; (i) chiral HPLC separation (Chiralcel AD column, 85% Heptane/
IPA + 0.1% TFA).
The corresponding trans isomers (3S,4R), isolated in
some cases in trace amounts as epimerized side-products
during the final hydrolysis step, displayed significantly
poorer activities against both PPARa and PPARc
receptors (data not shown). Our next goal was to define
the differences between the activity/liability profiles of
the 3- and 4-alkoxybenzyl azetidinone analogs. 4-Alk-
oxy analogs, such as 19 and 37, generally showed im-
proved potency at PPARc and relatively equivalent
potency at PPARa relative to their 3-alkoxy counter-
parts, such as 17 and 35. The 4-alkoxy analogs also dis-
played a generally superior CYP450 liability profile. For
example, the tert-butylphenyl analog 37 was a less po-
tent inhibitor of CYP 3A4 and 2C9 relative to 35.
MeO
BnO
OMe
NH
O
A
The N-arylation of azetidinone dimethyl acetal A in the
presence of Cu(OAc)2 and 4-methoxyphenylboronic
acid proceeded in mediocre (23%) yield. However, the
corresponding azetidinone carboxylates, (e.g., 23a) un-
dergo very efficient copper-mediated N-arylations with
substituted aryl boronic acids, using aryl/heteroaryl C–
N bond-forming conditions first established by Chan
and Lam,13 to give N-arylated azetidinones such as 34
(Table 1). This reaction was general and proceeded well
with a variety of aryl boronic acids to give the desired N-
arylated products in nearly quantitative yields.14
The SAR of the N-aryl group was also explored. Among
the aryl substituents examined, incorporation of the 4-
tert-butyl group (e.g., 35, 39–42) resulted in very potent
functional dual PPARa/c agonists, but unfortunately
also resulted in significantly increased CYP2C9 and
hERG liabilities of these analogs versus those with a 4-
methoxyphenyl group (e.g., 17). Among the N-aryl sub-
stituents studied in the 3-alkoxybenzyl azetidinone series,
The fully functionalized target acids 32 and 33 were
obtained from the N-arylated azetidinone esters 30
and 31 following a sequence similar to that described

Table 2. In vitro binding and transactivation activities against PPARa and PPARc15
O
3 4
OH
O
N
O
N
Ar
R1
O
meta or para
Compound Absol. Stereo. R1
Substitution Prep. Ref. Ar
Binding IC50 (lM)
Transactivationd EC50 lM
CYP P450 IC50 (lM)
hERG
b
IC50 (lM)
a
c
a
c
3A4a
2C9 2C19
GW 2331
Rosi
17
18
0.74 0.05
>15
0.60 0.04
0.043 0.02 >5
0.045 0.004
0.243 0.045
0.045 0.002
0.09 0.021
0.84 0.187
0.02 0.002
ND
17
18
19
20
35
36
37
38
39
40
41
42
43
44
45
46
3S,4S
H
H
H
H
H
H
H
H
meta
meta
para
para
meta
meta
para
para
16a
16a
16a
16a
16b
16c
16d
16d
16b
16b
16b
16b
16e
16e
16e
16e
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-t-Bu-phenyl
0.36 0.005 0.10 0.003 0.07 0.005
>15 1.1 0.118 >7.5
0.73 0.002 0.04 0.003 0.15 0.008
50/0.83
ND
2.2
ND ND
14 ND
ND
>80
ND
54
3R,4R
3S,4Sc
3R,4Rc
3S,4Sc
3R,4Rc
3S,4Sc
3R,4Rc
3S,4Sc
3S,4Sc
3S,4Sc
3S,4Sc
Racemic
Racemic
Racemic
Racemic
33/26
ND
>15
0.08
>15
3.4 0.31
0.04
0.8 0.02
>7.5
0.04
ND ND
0.23 ND
0.67 ND
N/D
6.2
0.12
17/19
20
4-t-Bu-phenyl
4-t-Bu-phenyl
5.4 0.723
0.41 0.023
0.004 0.0
0.50 0.048
0.04 0.005
0.10 0.033
0.04 0.011
ND
18.1
ND
2.1
0.79 0.037 0.11 0.024 0.01 0.001
>40/28
>40/>40
ND /19
ND /20
ND /12
4.7
2.3
3
ND
ND
4-t-Bu-phenyl
4-t-Bu-phenyl
>15
4.24 0.14
0.11 0.01
0.25 0.05
0.22 0.02
0.67 0.07
0.16 0.02
0.97 0.056
0.04 0.001
0.06 0.001
0.008 0.0
3-OMe meta
3-Cl meta
4-OMe meta
0.52 0.09
0.86 0.19
0.46 0.04
0.48 0.11
0.69 0.05
2.4 0.22
1.4 0.20
0.65 8.3
0.67 5.3
0.55 22
4-t-Bu-phenyl
4-t-Bu-phenyl
4-t-Bu-phenyl
1.8
3.2
4-Cl
H
meta
meta
meta
meta
meta
0.005 0.0002 0.06 0.008
0.41 2.8
ND ND
ND ND
ND ND
ND ND
1.3
4-Methoxyphenyl
4-Fluorophenyl
4-Chlorophenyl
0.14 0.011
0.18 0.048
0.03 0.003
0.13 0.002
0.07 0.001
ND
ND
ND
ND
ND
ND
H
0.18 0.011 0.11 0.008
0.36 0.05
0.23 0.02
H
0.23 0.024
0.09 0.008
ND
ND
H
6-Methoxypyridin-3-yl 1.3 0.20
a IC50s against two probe substrates, 7-benzyloxy-4-trifluoromethyl coumarin and 7-benzyloxyresorufin.
b hERG flux: a high-throughput FLIPR assay to address potassium channel activity; IC50 < 5 lM indicates high liability, 5–80 lM: moderate liability, and >80 lM low liability; ND, not determined.
c Stereochemical assignments were based on binding and transactivation activity differences and correlation to 3-alkoxybenzyl azetidinone series.
d All potent compounds (EC50 < 0.25 lM) had intrinsic activities of >90% in the PPARa and PPARc transactivation asssays. Intrinsic activity is defined as the activity of the ligand at 1 lM relative to the
primary standards at 1 lM; primary standards were GW-233117 for PPARa and rosiglitazone18 for PPARc.

W. Wang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1939–1944
1943
Table 3. In vivo data after a 14 day study in db/db mice dosed orally at 10 mpk once a day
Compound
Glucose lowering
TG lowering
Plasma conc. (lM)
Liver conc.c (nmol/g)
25
Adipose conc.c (nmol/g)
Muraglitazara
% change
p value
ꢀ54
ꢀ33
60.05
0
103
3
60.05
ꢀ43
17
35
% change
p value
2.8
10.4
7.4
0.29
<LLQ
60.05
ꢀ17
% change
p value
ꢀ52b
0.87
60.05
60.05
a Historical values.2
b After 3 weeks, the TG lowering was 61% (p 6 0.05).
c For plasma chemistry and tissue analysis protocols, see Ref. 7a.
ville, V.; Ryono, D.; Selan, F.; Hariharan, N.; Cheng, P.
J. Med. Chem. 2005, 48, 2248.
the 4-fluoro analog 44 (PPARc EC50 = 30 nM) showed a
6-fold increase in PPARc functional potency and no
change in PPARa potency relative to the 4-methoxy ana-
log 43 (PPARc EC50 = 180 nM). A basic substituent
such as 6-methoxypyridin-3-yl (46) was also well toler-
ated, as this analog retained potent dual PPARa/c ago-
nist activities. Based on their overall favorable activity
and liability profiles, compounds 17 (PPARa/c
EC50 = 70/90 nM) and 35 (PPARa/c EC50 = 40/
120 nM) were administered to female db/db mice in a
14-day chronic study (dosed orally q.d. at 10 mg/day; Ta-
ble 2). At this dose, compound 17 significantly decreased
fasting plasma glucose (ꢀ43%), essentially resulting in
the normalization of the hyperglycemic state. Interest-
ingly, for reasons not fully understood, 17 did not lower
plasma triglyceride levels, despite its potent PPARa
activity and having achieved reasonable drug concentra-
tions (10 nmol/g) in the liver, where PPARa is highly ex-
pressed. By comparison, muraglitazar at the same dose
resulted in a liver concentration of 25 nmol/g. Moreover,
compound 35, with a liver concentration of 7.4 nmol/g
decreased plasma triglycerides by 52%. This compound,
however, failed to produce any impact on glucose levels
despite its good PPARc functional activity. This was
likely due to low levels of drug observed in adipose, the
primary site of PPARc expression.
´
3. AZ-242: McIntyre, J. A.; Castan˜er, J.; Bayes, M. Drugs
Future 2003, 28, 959; (1st Scientific Sessions of the
American Diabetes Association, June 22–26, 2001, Phil-
adelphia, U.S.A., Poster numbers 483).
4. MK-767 KRP-297/MK-767: Nomura, M.; Kinoshita, S.;
Satoh, H.; Maeda, T.; Murakamo, K.; Tsunoda, M.;
Miyachi, H.; Awano, K. Bioorg. Med. Chem. Lett. 1999, 9,
533; Calkin, A. C.; Thomas, M. C.; Cooper, M. E. E.
Curr. Opin. Invest. Drugs 2003, 4, 444.
5. TAK-559 Sakamoto, J.; Kimura, H.; Moriyama, S.;
Imoto, H.; Momose, Y.; Odaka, H.; Sawada, H. Eur.
J. Pharmacol. 2004, 495, 17.
6. Colca, J. R. Expert Opin. Invest. Drugs 2007, 16, 129;
Nissen, S. E. J. Am. Med. Assoc. (JAMA) 2006, 295,
1998; Parra, D.; Beckey, C.; Thomas, T. J. Am. Med.
Assoc. (JAMA) 2006, 295, 1997; Najman, D. M. J. Am.
Med. Assoc. (JAMA) 2006, 295, 1997; Conlon, D. Br. J.
Diabetes Vascular Dis. 2006, 6, 135.
7. (a) Harrity, T.; Farrelly, D.; Tieman, A.; Chu, C.;
Kunselman, L.; Gu, L.; Ponticiello, R.; Cap, M.; Qu, F.;
Shao, C.; Wang, W.; Zhang, H.; Fenderson, W.; Chen, S.;
Devasthale, P.; Jeon, Y.; Seethala, R.; Yang, W.-P.; Ren,
J.; Zhou, M.; Ryono, D.; Biller, S.; Mookhtiar, K. A.;
Wetterau, J.; Gregg, R.; Cheng, P. T.; Hariharan, N.
Diabetes 2006, 55, 240; (b) Tozzo, E.; Ponticiello, R.;
Swartz, J.; Farrelly, D.; Zebo, R.; Welzel, G.; Egan, D.;
Kunselman, L.; Peters, A.; Gu, L.; French, M.; Devast-
hale, P.; Janovitz, E.; Staal, A.; Harrity, T.; Belder, R.;
Cheng, P.; Whaley, J.; Taylor, S.; Hariharan, N.
J. Pharmacol. Exp. Ther. 2007, 3211, 107; (c) Hosagraha-
ra, V. P.; Chandrasena, G.; Chang, S. Y.; Koplowitz, B.;
Hariharan, N.; Cheng, P. T. W.; Humphreys, W. G.
Xenobiotica 2006, 36, 1227.
8. Staudinger reaction: (a) Venturini, A.; Gonzalez, J. Mini
Rev. Org. Chem. 2006, 3, 185; (b) Singh, G. S. Tetrahedron
2003, 59, 7631.
9. Adlington, R. M.; Baldwin, J. E.; Becker, G. W.; Chen, B.;
Cheng, L.; Cooper, S. L.; Hermann, R. B.; Howe, T. J.;
McCoull, W.; McNulty, A. M.; Neubauer, B. L.; Prit-
chard, G. J. J. Med. Chem. 2001, 4410, 1491.
In conclusion, a novel series of conformationally-con-
strained, azetidinone-acid dual PPARa/c agonists with
a range of sub-type selectivities in vitro was discovered.
The preferred stereochemistry was determined to be
3S,4S. Compound 17 displayed significant plasma glu-
cose lowering while compound 35 displayed robust plas-
ma triglyceride lowering after chronic administration in
db/db mice. Additionally, a novel and high-yielding
method for the N-arylation of azetidinone esters has
been discovered.
10. PDB Deposition number is 2REW.
References and notes
11. Yin, J.; Buchwald, S. Org. Lett. 2000, 2, 1101.
12. Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G.
Tetrahedron Lett. 2002, 43, 3091.
13. Lam, P.; Clark, C.; Saubern, S.; Adams, J.; Winters, M.;
Chan, D.; Combs, A. Tetrahedron Lett. 1998, 39, 2941;
Chan, D. M. T.; Lam, P. Y. S. In Boronic Acids; Hall, D.
G., Ed.; Wiley-VCH, Verlag GmbH & Co.; KGaA,
Weinheim, 2005; p 205, Chapter 5.
14. Typical procedure. To a solution of azetidinone 23a (270 mg,
0.75 mmol) in dichloroethane (12 mL) were added 4-tert-
butylphenylboronic acid (377 mg, 2.11 mmol), Cu(OAc)2
(160 mg, 0.88 mmol), Et3N (0.511 mL, 3.67 mmol), and
1. Recent PPAR reviews: (a) Gervois, P.; Fruchart, J.-C.;
Staels, B. Nat. Clin. Practice Endocrinol. Metab. 2007, 3,
145; (b) Pershadsingh, H. A. Treatments Endocrinol. 2006,
5, 89; (c) Cheng, X.-C.; Xu, W.-F. Drugs Future 2006, 31,
875.
2. Devasthale, P. V.; Biller, B.; Chen, S.; Jeon, Y.; Qu, F.;
Shao, C.; Wang, W.; Zhang, H.; Farrelly, D.; Golla, R.;
Grover, G.; Harrity, T.; Ma, Z.; Moore, L.; Ren, J.;
Seethala, R.; Cheng, L.; Sleph, P.; Sun, W.; Tieman, A.;
Doweyko, A.; Chandrasena, G.; Humphreys, G.; Sasse-

1944
W. Wang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1939–1944
˚
pyridine (0.297 mL, 3.67 mmol) and 4 A molecular sieves
16. (a) Following Scheme 1; (b) Following Scheme 2, via t-
Bu ester (+)-23b; (c) Following Scheme 2, via t-Bu
ester (ꢀ)-23b; (d) Following Scheme 2, via Me ester
24a to 33 followed by chiral HPLC separation (Chi-
ralcel AD column, 85% Heptane/IPA + 0.1% TFA) to
37 and 38; (e) Following Scheme 2, via racemic Me
ester 23.
17. Brown, P. J.; Smith-Oliver, T. A.; Charifson, P. S.;
Tomkinson, N. C. O.; Fivush, A. M.; Sternbach, D. D.;
Wade, L. E.; Orband-Miller, L.; Parks, D. J.; Blanchard,
S. G. Chem. Biol. 1997, 4, 909.
(200 mg; pre-dried at 400 °C overnight). Air was allowed to
pass into the reaction mixture, which was stirred at room
temperature for 5 h. The solid was filtered off (Celite) and
the filtrate was concentrated in vacuo to give a crude
product which was purified by flash chromatography (silica
gel, 100% Hexanes to 75% Hexanes/EtOAc) to give the
desired product as a white foam.
15. For in vitro binding and transactivation protocols used,
see: (a) Devasthale, P. V.; Chen, S.; Jeon, Y.; Qu, F.;
Ryono, D. E.; Wang, W.; Zhang, H.; Cheng, L.; Farrelly,
D.; Golla, R.; Grover, G.; Ma, M.; Moore, L.; Seethala,
R.; Sun, W.; Doweyko, A. M.; Chandrasena, G.; Sleph,
P.; Hariharan, N.; Cheng, P. T. W. Bioorg. Med. Chem.
Lett. 2007, 17, 2312; (b) Refs. 2 and 7a.
18. Lehmann, J. M.; Moore, L. B.; Smith-Oliver, T. A.;
Wilkison, W. O.; Willson, T. M.; Kliewer, S. A. J. Biol.
Chem. 1995, 270, 12953.