2-Alkoxydihydrocinnamates as PPAR agonists. Activity modulation by the incorporation of phenoxy substituents

Article abstract of DOI:10.1016/j.bmcl.2004.10.042

Herein we describe a series of potent and selective PPARγ agonists with moderate PPARα affinity and little to no affinity for other nuclear receptors. In vivo studies in a NIDDM animal model (ZDF rat) showed that these compounds are efficacious at low doses in glucose normalization and plasma triglyceride reduction. Compound 1b (LY519818) was selected from our SAR studies to be advanced to clinical evaluation for the treatment of type II diabetes. Herein we describe a series of potent and selective PPARγ agonists with moderate PPARα affinity and little to no affinity for other nuclear receptors. In vivo studies in a NIDDM animal model (ZDF rat) showed that these compounds are efficacious at low doses in glucose normalization and plasma triglyceride reduction. Compound 1b (LY519818) was selected from our SAR studies to be advanced to clinical evaluation for the treatment of type II diabetes.

Full text of DOI:10.1016/j.bmcl.2004.10.042

Bioorganic & Medicinal Chemistry Letters 15 (2005) 51–55
2-Alkoxydihydrocinnamates as PPAR agonists. Activity
modulation by the incorporation of phenoxy substituents
a,
Jose A. Martın, Dawn A. Brooks, Lourdes Prieto, Rosario Gonzalez, Alicia Torrado,
b
a
a
a
*
´
´
Isabel Rojo, Beatriz Lopez de Uralde, Carlos Lamas, Rafael Ferritto,
´
a
a
a
a
´
a
a
c
b
´
´
Marıa Dolores Martın-Ortega, Javier Agejas, Francisco Parra, John R. Rizzo,
Gary A. Rhodes,b Roger L. Robey,b Charles A. Alt,b Samuel R. Wendel,b Tony Y. Zhang,b
Anne Reifel-Miller,b Chahrzad Montrose-Rafizadeh,b Joseph T. Brozinick,b
Eric Hawkins,b Elizabeth A. Misener,b Daniel A. Briere,b Robert Ardecky,d
James D. Fraserd and Alan M. Warshawskyb
aLilly Research Laboratories, A Division of Eli Lilly & Company, Lilly S.A., Alcobendas 28108, Madrid, Spain
bLilly Research Laboratories, A Division of Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
c
´
´
´
´
Departamento de Quımica Organica, Universidad, de Alcala, 28871 Alcala de Henares, Madrid, Spain
dLigand Pharmaceuticals, 10275 Science Center Drive, San Diego, CA 92121, USA
Received 18 May 2004; revised 7 October 2004; accepted 13 October 2004
Available online 2 November 2004
Abstract—Herein we describe a series of potent and selective PPARc agonists with moderate PPARa affinity and little to no affinity
for other nuclear receptors. In vivo studies in a NIDDM animal model (ZDF rat) showed that these compounds are efficacious at
low doses in glucose normalization and plasma triglyceride reduction. Compound 1b (LY519818) was selected from our SAR studies
to be advanced to clinical evaluation for the treatment of type II diabetes.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
ureas, to produce an increase in insulin levels that event-
ually overcome the impaired glucose transport system.4
Other treatments which are based on the decrease of
plasma glucose without the increase of insulin levels in-
clude a-glycosidase inhibitors and metformin.5
Noninsulin dependent diabetes mellitus (NIDDM) is a
major progressive metabolic disorder that affects 5–
10% of adults over the age of 30 in most populations.1
The prevailing incidence of the disease is in the elderly
population of developed countries with the main cause
being a high-fat western diet combined with a sedentary
lifestyle.2 This etiology is shared by other major diseases
such as obesity and cardiovascular disorders. The disease
is characterized by malfunctions in insulin-mediated glu-
cose uptake in muscle and adipose tissues. The basic ap-
proach to treating NIDMM focuses on the control of
blood glucose levels in order to reduce the incidence of
the microvascular and macrovascular complications that
define this syndrome.3 Some treatments are based on the
administration of insulin secretagogues, such as sulfonyl
Recently, compounds containing the thiazolidinedione
(glitazone) moiety, were found to reduce plasma glucose
levels in both animal models of diabetes and in human
patients with NIDDM without increasing plasma insu-
lin levels and without causing hypoglycemia.6 Pioglit-
azone and rosiglitazone are marketed currently as
treatments for NIDMM. The molecular target of the
glitazones was unknown until the first compounds of
the class were in the late-stages of clinical development.7
These compounds were determined to be potent agonists
of the peroxisome proliferator-activated receptor gam-
ma (PPARc), a member of a super family of nuclear
transcription factors that include steroid, retinoid, and
thyroid hormone receptors.8 There are three known
PPAR subtypes; PPARa, PPARc, and PPARd (also
Keyword: PPARc agonist.
Corresponding author. Tel.: +34 91 663 3418; fax: +34 91 663
3411; e-mail: martin_jose_alfredo@lilly.com
*
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.10.042

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J. A. Martın et al. / Bioorg. Med. Chem. Lett. 15 (2005) 51–55
52
known in the literature as PPARb). With its primary
function related to lipid homeostasis, PPARa is distri-
buted mainly in the liver, heart, and kidney. In contrast,
PPARc is predominantly expressed in adipose tissue and
muscle, and PPARd is expressed ubiquitously. Although
the exact mechanism for insulin sensitization by PPARc
ligands remains unclear, it is known that the differentia-
tion of preadipocytes to adipocytes is induced in cul-
tured cells following the binding of synthetic ligands to
the receptor.9
aldehyde and methyl alkoxyacetate derivatives gave
the trifluoroacetic ester after a direct quench with tri-
fluoroacetic anhydride. Exhaustive hydrogenolysis gave
the racemic headpiece 2a. Resolution of the headpiece
2a was achieved by crystallization of the acid derivative
obtained by saponification of 2a-acid as cinchonidine
salt. After isolation of the free acid, treatment with eth-
anol and sulfuric acid provided the desired ester head
piece Ha. Racemic headpiece rac-Hb was prepared in a
similar two-step synthesis by elimination of the aldol
derivative using mesyl chloride/triethylamine, followed
by olefin reduction with magnesium in methanol prior
to the debenzylation.12,10d The further synthesis using
this headpiece (see below) gave the racemic final com-
pound that was resolved by chiral HPLC to afford com-
pound 1e. Compound Hc was prepared according with
the method previously described.13 The 3-chloro analog
Hd was obtained from Ha directly by chlorination with
N-chlorosuccinimide.
In our investigations, we sought PPARc agonists outside
the glitazone class that would produce improved glyce-
mic and lipid control in animal models of diabetes that
could be translated to man. During our search, we found
that the para-biphenoxypropoxy 2-methoxyhydrocin-
namic acid 1a10 was a high affinity ligand for PPARc,
which behaved as an agonist in the cell-based efficacy
assay. Furthermore, 1a showed modest PPARa agonist
activity, which could lead to an improved triglyceride
and cholesterol profile.11 Greater than 65-fold selectivity
versus PPARd was observed. Compound 1a also showed
a promising in vivo potency (ED50 = 1.6mg/kg) in the
Zucker diabetic fatty rat, our primary model to evaluate
glucose and triglyceride lowering.
Tailpieces Ta–c containing di-ether linkers were pre-
pared using the corresponding phenols, 1,3-dibromo-
propane, and powdered potassium carbonate in methyl
ethyl ketone. Ta–c and Ha–d were coupled using pow-
dered potassium carbonate in DMF at room tempera-
ture. Subsequent hydrolysis, without purification of
the coupled product, afforded 1a–f.
In this paper, we describe new SAR findings around the
lipophilic tailpiece of the 2-alkoxydihydrocinnamate
class that led to potent PPARc agonists in vitro and
effective compounds for the control of glucose and lipid
levels in a diabetes animal model.
For compounds with monoether linkers (1g–h),
palladium catalyzed Sonogashira conditions for the
coupling of alkynes with the aryl iodo-headpiece were
employed. Specifically, L-p-iodophenylalanine14 was
converted into the methoxylated aryl iodide He
via sequential hydroxydeamination and O-methylation.
This compound served as a pivotal starting material
for the preparation of compounds with a triple bond
in the linker.
2. Chemistry
Compounds 1a–h were synthesized as described in
Scheme 1. The aldol condensation of 4-benzyloxybenz-
O
O
O
O
O
OMe
CHO
a,b
e
f,g,h
OMe c,d
OEt
OEt
OH
OEt
OR1
OMe
OMe
NH2
BnO
HO
HO
HO
I
R2
R2
2a R1=Me, R2=H
rac-Hb R1=Me, R2=OMe (42%)
Cl
He (28%)
Hd (62%)
Ha (14%)
O
R3
R3
j,k
OH
OR1
R3
O
Ta R3=Ph
Tb R3=OPh
Tc R3=C(O)Ph
Td n=1
O
O
O
Br
i
R2
OEt
Ta-c
1a-f
79-84%
24-82%
OEt
Hc (Ref 13)
l
O
HO
Te n=2
PhO
OH
m,k
OH
R3=OPh
PhO
OMe
O
n
O
n
Td-e
1g-h
21%, 93%
64%, 70%
Scheme 1. (a) Reagents and conditions: methyl a-methoxyacetate, NaHDMS, THF, À78°C, then TFAA for 2a, or MsCl/TEA for Hb; (b) H2, Pd–C,
EtOAc for 2a, or Mg/MeOH and then H2, Pd–C, MeOH for Hb; (c) saponification of 2a, cinchonidine crystallization, and acid isolation; (d) H2SO4,
ethanol; (e) NCS, CH3CN; (f) I2, NaIO3, H2SO4, AcOH; (g) NaNO2, H2SO4; (h) MeI, NaH, THF; (i) 1,3-dibromopropane, 3-butynyl p-
toluenesulfonate, or 5-chloro-1-pentyne, K2CO3, MEK; (j) Ha-d, K2CO3, DMF, rt, or MeCN at 85°C; (k) 5N NaOH, EtOH. For 1e, chiral HPLC
separation; (l) K2CO3, MEK; (m) He, Pd(PPh3)4, CuI, piperidine.

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J. A. Martın et al. / Bioorg. Med. Chem. Lett. 15 (2005) 51–55
53
3. Results and discussion
1d than for 1b at 0.1, 0.3, and 1mg/kg doses. The varia-
tion of the central ring by introducing a substituent at
the 2-position did not produce notable changes in the
in vitro parameters or an improvement in the in vivo po-
tency (1e versus 1b and 1c versus 1f). A chlorine atom
does not change substantially the affinity while the intro-
duction of a methoxy group slightly increases (3-fold)
the PPARc affinity.
Several series of nonTZD PPARc agonists have been
described.15 Some of these series contain the 2-alkoxy-
cinnamate head piece containing different aromatic tail-
pieces.10 In our efforts to further investigate the
influence of the distal aromatic ring on euglycemic activ-
ity, we found that compound 1a (Table 1), containing a
para-biphenyloxy tailpiece,16 was a selective PPARc
agonist (binding IC50 = 21nM, CTF potency11a
EC50 = 154nM) with weak human PPARa and weaker
PPARd activities and with no activity for any other nu-
clear receptor evaluated (RARa, RXRa, AR, PR, ERa,
GR, MR). The in vivo potency of 1a measured in the
ZDF model was approximately 3.6-fold lower than rosi-
glitazone (ED50 = 0.41mg/kg). Encouraged by this pre-
liminary result, we synthesized a series of analogs of
1a in order to improve its in vitro and in vivo parame-
ters. The results are summarized in Table 1.
The linker that joins the two aromatic ends of the mole-
cule was also examined. Conceptually, modification of
the linker could change the conformation of the mole-
cule substantially, and therefore, alter its PPAR binding,
selectivity, and functional activity as well as its in vivo
profile.18 The oxygen directly bound to the central aryl
ring was replaced by an alkyne moiety to provide com-
pounds 1g and 1h. Compound 1h demonstrated slightly
better (3-fold) PPAR binding than 1b with comparable
in vivo potency. Interestingly, the length of the linker
does not affect the PPARa/PPARc selectivity profile of
1g and 1h. These compounds with the alkyne linkers
are still flexible enough to be adapted to both PPARa
and PPARc receptors.
Replacement of the biphenyl moiety by phenoxyphenyl
to give 1b produced a 4-fold decrease in PPARa affinity
while the PPARc binding is maintained; however, 1b
showed more than 10-fold improvement in the in vivo
potency. The change of the biphenoxy moiety by the
benzophenone group (1c) resulted in an increase in affin-
ity for both PPARa and PPARc but did not translate to
further improvement in the in vivo potency. Substitution
of the methoxy group at the C-2 position of the propa-
noic acid for an ethoxy (1d versus 1b) gave a 3-fold de-
crease in PPARc binding but did not change other in
vitro parameters substantially. However, the in vivo po-
tency for the ethoxy compound improved approximately
7-fold. Similar effects resulting from a change of the
methoxy to the ethoxy group have been observed previ-
ously in a related series.10a,17 This effect could be due to
a difference in exposure. Plasma levels of compound in
the efficacy studies (single point determination after 7
days of treatment) are approximately 2-fold higher for
Figure 1 shows the in vivo profile of compound 1b after
daily oral administration to Zucker diabetic fatty rats at
different doses. Figure 1 (left) shows the plasma glucose
change from vehicle compared with rosiglitazone treated
animals at 7 days of treatment, and the graph on the
right shows the corresponding parameters for plasma
triglyceride. Both rosiglitazone and compound 1b nor-
malized plasma glucose at 3mg/kg (plasma glucose val-
ues of 180 and 179mg/dl, respectively). A calculated
ED50 for compound 1b of 0.10 0.04mg/kg was signi-
ficantly lower than the ED50 of the standard compound
Rosiglitazone (0.41 0.10mg/Kg).19 The triglyceride
lowering parallels the glucose reduction at each dose,
in agreement with a PPARc mediated effect in the
ZDF rat. Compound 1b is a weak h-PPARa agonist,
Table 1. Binding IC50, cotransfection efficacy, and in vivo data for compounds 1a–h
R1/R2/R3 or (n)
h-PPARc
h-PPARa
a,b
h-PPARdd In vivo
CTF eff (%)c IC50
EC50
CTF eff (%)c IC50
ZDF rat ED50 (mg/Kg)f
0.41 0.10
NT
1.5e
0.10 0.04
a,b
a,b
a,b
a,b
IC50
EC50
Rosiglitazone
Fenofibric acid
1a Me/H/Ph
70
>10,000
268
—
100
11
>10,000
>10,000
568 50
—
>10,000
1100 147 42
9.11
75 20
—
NT
5
2
5
8
4
2
2
3
4
21
34
5
3
3
1
9
1
1
2
2
154 30 84
361 35 77
260 20 76
282 29 85
185 25 87
305 34 83
103 11 74
239 45 77
2
4
2
2
1
3
1
2
1391 127
1916 148
2324 476
1569 447
7502 1505
1507 23
3938 206
4123 163
1b Me/H/OPh
1c Me/H/C(O)Ph
1d Et/H/OPh
2711 364 2816 35
470 20 2870 32
43
27
30
35
36
33
35
0.18 0.06
0.015 0.04
0.12 0.02
0.29 0.09
0.08 0.02
0.07 0.02
44
1686 168 2754 76
1349 357 2152 87
1e Me/MeO/OPh 13
1f Me/Cl/C(O)Ph
1g (1)
1h (2)
5
13
7
309 38
2713 30
1154 182 1880 86
770 156 2622 94
Head- and tailpieces of the compounds (see Scheme 1).
a Mean for at least three determinations standard error.
b Values given in nM. Competitive displacement binding assays were performed using scintillation proximity assay (SPA) technology, PPAR
receptors, and corresponding radiolabeled ligands.
c Maximum efficacy as % of the maximum efficacy of the standard.
d None of the compounds were efficacious in the PPARd CTF assay.
e Estimated value.
f Statistical significance was determined by one-way analysis of variance (ANOVA). When statistical significance was detected with this method,
group differences were determined by Neuman–Keuls post-hoc analyses.

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J. A. Martın et al. / Bioorg. Med. Chem. Lett. 15 (2005) 51–55
54
Plasma Glucose Change from Vehicle Treatment in Male ZDF Rats After
One Week Administration of LY519818 or Rosiglitazone
Plasma Triglycerides Change from Vehicle Treatment in Male ZDF Rats
After One Week Administration of LY519818 or Rosiglitazone
50
0
2
1
Rosiglitazone
LY519818 (1b)
Rosiglitazone
LY519818 (1b)
-50
0
-100
-150
-200
-250
-300
-350
-400
-1
-2
-3
-4
-5
-6
-7
0.1
1
3
10
0.1
0.3
1
3
10
0.3
Dose (mg/kg)
Dose (mg/kg)
Figure 1. Plasma glucose (left) and triglycerides (right) changes from vehicle treatment in 8-week-old male ZDF rats dosed with vehicle (1%
carboxymethylcellulose/0.25% Tween 80), LY519818, or rosiglitazone for 7 days (N = 5 per group). Blood samples were taken via tail snip, and
plasma was analyzed on a Hitachi 912 metabolic analyzer for glucose and triglyceride content. Plasma glucose and triglyceride levels for vehicle
treated rats were 456mg/dL and 6.9mmol/L, respectively.
which could lead to a better cholesterol profile in hu-
mans. Compound 1b has better affinity for h-PPARa
and more potent although less efficacious agonist activ-
ity than the well characterized PPARa agonist fenofi-
brate (Table 1). Because fenofibrate lowers total
cholesterol, LDL-C, VLDL-C, and total triglycerides
in addition to increasing HDL-C following administra-
tion to humans,20 we anticipate that compound 1b could
demonstrate beneficial lipid parameters in addition to its
anti-diabetic activities when tested in patients with type
2 diabetes. The lack m-PPARa efficacy in our cotrans-
fection assay (14 4%) precluded evaluation in our
PPARa responsive animal model; however, we consider
compound 1b as a PPARc-dominant dual agonist with
confirmation of its beneficial PPARa activities coming
from on-going clinical trials.
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of his advice in this work.

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