4,4-Dimethyl-1,2,3,4-tetrahydroquinoline-based PPARα/γ agonists. Part. II: Synthesis and pharmacological evaluation of oxime and acidic head group structural variations

Article abstract of DOI:10.1016/j.bmcl.2009.03.143

Type-2 diabetes (T2D) is a complex metabolic disease characterized by insulin resistance in the liver and peripheral tissues accompanied by a deficiency in pancreatic β-cells. Since their discovery, three subtypes of peroxisome proliferator activated receptors have been identified, namely PPARα, PPARγ and PPARβ/(δ). In this study, we were interested in designing novel PPARγ selective agonists and/or dual PPARα/γ agonists. Based on the typical topology of synthetic PPAR agonists, we focused our design approach on using 4,4-dimethyl-1,2,3,4-tetrahydroquinoline as a novel cyclic scaffold with oxime and acidic head group structural variations.

Full text of DOI:10.1016/j.bmcl.2009.03.143

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2683–2687
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
4,4-Dimethyl-1,2,3,4-tetrahydroquinoline-based PPARa/c agonists. Part. II:
Synthesis and pharmacological evaluation of oxime and acidic head group
structural variations
Cécile Parmenon a, Jérôme Guillard a, Daniel-Henri Caignard b, Nathalie Hennuyer c, Bart Staels c,
Valérie Audinot-Bouchez d, Jean-Albert Boutin d, Catherine Dacquet e, Alain Ktorza e,
Marie-Claude Viaud-Massuard a,
*
a UMR 6239 GICC, Laboratoire de Chimie Organique,UFR des Sciences Pharmaceutiques, 31 avenue Monge, 37200 Tours, France
b Etudes Extérieures et Alliances stratégiques, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy sur Seine, France
c Département d’Athérosclérose, U545 Institut Pasteur de Lille, 1 Rue du Pr. Calmette, 59019 Lille Cedex, France
d Division de Recherche Pharmacologie Moléculaire et Cellulaire, 125 Chemin de Ronde, 78290 Croissy sur Seine, France
e Division Maladies Métaboliques, Institut de Recherches Servier, 11 Rue des Moulineaux, 92150 Suresnes, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Type-2 diabetes (T2D) is a complex metabolic disease characterized by insulin resistance in the liver and
Received 16 December 2008
Revised 25 March 2009
Accepted 27 March 2009
Available online 1 April 2009
peripheral tissues accompanied by a deficiency in pancreatic b-cells. Since their discovery, three subtypes
of peroxisome proliferator activated receptors have been identified, namely PPAR
a
, PPAR
c
and PPARb/(d).
ago-
In this study, we were interested in designing novel PPAR selective agonists and/or dual PPARa/c
c
nists. Based on the typical topology of synthetic PPAR agonists, we focused our design approach on using
4,4-dimethyl-1,2,3,4-tetrahydroquinoline as a novel cyclic scaffold with oxime and acidic head group
structural variations.
Keywords:
PPARs
Terahydroquinoline
Oxime
Ó 2009 Elsevier Ltd. All rights reserved.
The peroxisome proliferator activated receptors are ligand-acti-
vated transcription factors belonging to the nuclear hormone
superfamily.1 Since their discovery in 1990 by I. Isseman and S.
We have recently reported the design, synthesis and biological
data of a novel 4,4-dimethyl-1,2,3,4-tetrahydroquinoline-based
series of PPARc partial agonists and PPARa/c
dual agonists.18 This
Green2 three subtypes of PPARs have been identified, and desig-
study has led to the identification and optimization of lead com-
,
nated
a,
c
and d (b). These receptors have aroused considerable
pound 1, which has noteworthy dual-activity on both subtypes.
interest in pharmaceutical research due to their extensive involve-
ment in glucose and lipid homeostasis3–6, and a number of agonists
in this class have progressed to the clinical phase, and been mar-
keted as anti-diabetic drugs.7,8 The success of the hypolipidemic fi-
brates and glitazones class of insulin sensitizers (full-agonists of
Our lead compound 1 possesses the
acid head group, which is a potent binding moiety for both PPAR
and PPAR . In order to investigate the impact of variations on the
a-ethoxy-b-phenylpropionic
a
c
transactivation activity, we first changed the chain length of the
oxime of 6-benzoyl-1,2,3,4-tetrahydroquinoline without changing
the acidic head, and we subsequently decided to modify this part
of the structure. Here, we report the synthesis and in vitro and
in vivo biological evaluation of a new series of tetrahydroquinolines.
The synthesis of all the oximes followed on the condensation of
the corresponding alkoxylamines on precursor 2, as previously de-
scribed18 (Scheme 1). Saponification of intermediary esters using
an aqueous solution of lithium hydroxide quantitatively generated
PPARa1 and PPARc 9,10
respectively) has incited pharmaceutical
,
companies to concentrate on developing more potent and dual act-
ing agonists belonging to these two subtypes.6 In the past decade,
dual-acting PPARa/c agonists (e.g., Tesaglitazar, Muraglitazar,
Fig. 1) have been viewed as a very attractive option in the treat-
ment of dyslipidemic type-2 diabetes.6,8,11–16 Moreover such com-
pounds might also avoid or reduce the main side effects (weight
gain or edema) induced by the full PPAR
c
agonists, TZDs.17
a-hydroxy-acids 3a–c.
The general strategy of modifying the acidic head is outlined in
Scheme 2. In this procedure, appropriate phenols 5a–d were cou-
pled with the bromo key intermediate 4 under standard substitu-
tion conditions. Compounds 6a–d were further functionalized in
the required oxime by treatment with the convenient hydroxyl-
* Corresponding author. Tel.: +33 247367227; fax: +33 247367229.
E-mail address: marie-claude.viaud-massuard@univ-tours.fr (M.-C. Viaud-Mas-
suard).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.143

2684
C. Parmenon et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2683–2687
O
O
OH
HN
N
O
O
Farglitazar
O
O
O
O
N
O
O
OH
O
O
OH
S
N
O
O
O
O
Tesaglitazar
Muraglitazar
O
(S)
O
OH
O
N
1
N
O
Figure 1. Structures of a PPAR
c
selective agonist, two PPAR
a
/
c
dual agonists (aborted during clinical phase III), and lead compound 1.
O
O
(S)
(S)
A
A
OH
O
R
O
R
O
i, ii
N
N
68-77%
N
O
OR2
3aR2
3bR2
3cR2
=
=
=
2 A = CH, R = OEt
Scheme 1. Reagents and conditions: (i) R2O–NH2, HCl, pyridine, rt, 5 h; (ii) LiOH, H2O, THF, 24–36 h.
amine hydrochloride in pyridine, and the desired acids 8a–d were
obtained after lithium hydroxide mediated saponification.
The synthesis of synthon 4 was conducted in five steps, and is
detailed in our previous paper.18b
quantitatively. Insertion of trifluoroethanol catalysed by rhodium
acetate (II) generated intermediate 12, with a modest yield.19 Fi-
nally, catalytic debenzylation under a hydrogen atmosphere in eth-
anol yielded the desired compound, 5b.
In the first analog we designed, the ethoxy-ether was replaced
by the acetate analog. Phenol 5a was thus prepared in three steps
Supported by the interesting results with Farglitatzar (Fig. 1) we
decided to introduce the N-(benzoylphenyl)-tyrosine scaffold into
with 85% yield, starting from commercially available O-benzyl-
L
-
our cyclic tail as the selective PPARc agonist. Thus, DL-tyrosine
tyrosine, as shown in Scheme 3. Treatment with isoamylnitrite
in a mixture of acetic acid and chloroform yielded 9, which was
subsequently hydrogenated using palladium on charcoal as
catalyst.
was first esterified under standard conditions, and the resulting
amino-ester 13 was then condensed on 2-benzoylcyclohexanone.
Aromatization was carried out in situ, and generated the desired
phenol 5c with a yield of 49%.20
The trifluoroethoxy homolog of 1 was next envisaged, and re-
quired the synthesis of the corresponding phenol 5b. This was gen-
Once Muraglitazar (Fig. 1) had been described in the literature
as the most potent PPARa/c dual agonist, we synthesized one of
erated from O-benzyl-
in Scheme 4.
After classical esterification in ethanol, compound 10 was trea-
ted with isoamylnitrite in chloroform using a catalytic amount of
acetic acid. Under these conditions, diazoester 11 was isolated
L
-tyrosine according to the sequence shown
its homologs for inclusion in our series. As shown in Scheme 6,
phenol 4d was prepared in a four-step sequence, starting from
commercially-available 4-benzyloxy-benzaldehyde. First, treat-
ment of the aldehyde with glycine ethyl ester in methanol followed
by the reductive action of sodium borohydride gave the amino-es-

C. Parmenon et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2683–2687
2685
O
A
R1
O
Br
O
O
N
N
i
A
R1
O
+
HO
O
O
4
5a-d
6a-d
O
O
A
R1
O
A
R1
OH
O
O
N
N
ii
iii
N
N
OR 2
OR 2
7a-d
8a-d
Scheme 2. Reagents and conditions: (i) K2CO3, DMF, 60 °C, 24–48 h; (ii) CH3O–NH2.HCl, pyridine, reflux, 3–5 h; (iii) LiOH.H2O, THF/H2O, rt, 24–36 h.
O
O
O
i
ii
OH
O
OH
O
OH
O
O
NH2
85%
BnO
100%
HO
BnO
9
5a
Scheme 3. Reagents and conditions: (i) i-C5H11ONO, AcOH/CHCl3, rt, 36 h; (ii) H2, Pd/C, EtOH, rt, 18 h.
O
O
O
ii
i
O
O
OH
N2
NH2
NH2
BnO
BnO
BnO
100%
100%
10
11
O
F
O
O
O
F
iv
100%
iii
33%
O
F
O
F
HO
BnO
F
F
12
5b
Scheme 4. Reagents and conditions: (i) SOCl2, EtOH, rt, 12 h; (ii) i-C5H11ONO, AcOH cat., CHCl3, reflux, 30 min; (iii) Rh2(OAc)4, CF3CH2OH, reflux, 2 h; (iv) H2, Pd/C, EtOH, rt,
12 h.
O
O
O
i
ii
OH
O
O
NH2
NH2
HN
100%
49%
HO
HO
HO
O
13
5c
Scheme 5. Reagents and conditions: (i) SOCl2, EtOH, rt, 18 h; (ii) 2-benzoylcyclohexanone, Pd/C, anisole, reflux, 3 h.

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C. Parmenon et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2683–2687
O
O
N
O
i, ii
iii, iv
78%
N
H
O
H
O
HO
O
O
79%
BnO
BnO
14
5d
Scheme 6. Reagents and conditions: (i) glycine-ethyl ester hydrochloride, Et3N, MeOH, rt, 5 h; (ii) NaBH4, MeOH, rt, 18 h; (iii) ethyl chloroformate, Et3N, THF, rt, 1 h; (iv) H2,
Pd/C, EtOH, rt, 12 h.
Table 1
Activity of compounds 6a–d in a cell-based transactivation assay against human PPAR
R1
R2
Binding PPAR
c
Transactivation EC50 nMb(% activity)
a
Compound
A
Ki (nM)
hPPAR
a
hPPARc
1
CH
CH
CH
CH
CH
CH
CH
N–CH2
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OAc
OCH2CF3
NH–Ph–CO–Ph
C(O)OEt
CH3
CH2–CH@CH2
Bn
18
114 (63)
73(152)
34(137)
9(145)
na
1000 (50)
10,000 (11)
na
7.85 (95)
13(150)
7(124)
7.52(165)
na
125 (100)
14 (72)
10 000 (69)
3a
3b
3c
8a
8b
8c
8d
54.2
18.4
254
>10,000
33
CH2-cyclopropyl
CH3
CH3
CH3
H
54
>10,000
a
Values are means of three experiments (na = not active).
b
Refers to the maximal activity obtained with each compound expressed as a percentage of the maximum activity of Rosiglitazone at 10À6 M for PPAR
c
and of WY 14,643
at 10À5 M for PPAR
a.
ter product 14 with a 79% yield. Condensation of ethyl chlorofor-
mate generated the carbamate, which was finally debenzylated
to produce phenol 5d (Scheme 5).
these compounds have shown a better metabolic stability than
compound 1; in this series 3c displays the best results. These val-
ues allowed us to confirm that the major degradation site of our
compounds is located on the methyl oxime ether (see Table 2,
compound 1).
Compounds were characterized by determining the binding
affinity to human PPAR
c
, using a competitive binding assay with
[3H]rosiglitazone, an appropriate radioligand for PPAR
c
. The bind-
With a good affinity for the PPARc receptor (Ki = 33 nM),
ing profiles of compounds were compared to those of the lead
compound 8b displays the same dual-agonist pharmacological
derivative 1. Functional activity was measured in a transient trans-
profile compared to derivative 1. Nevertheless, the transactiva-
fection assay using pGAL4hPPAR
a
and pGAL4hPPAR
c. The results
tion values, 100% and 50% for PPARc and PPARa, respectively,
are given in Table 1.
associated with EC50 values of 125 nM and 1000 nM, indicate
With a good affinity for PPAR
is a dual agonist PPAR with the same pharmacological profile as
compound 1. Compound 3b confirms this finding by increasing the
activity of PPAR (137% of transactivation at 34 nM).
In this series, compound 3c seems to be the best analog of lead
compound 1. Indeed, although the binding constant, Ki (254 nM), is
c (Ki = 54.2 nM), the allyl analog 3a
low agonist power towards these receptors. Finally, compound
8c shows good selectivity for PPARc, but this derivative was
not evaluated in vivo with regard to its absorption value with
CaCo2 cells (22%). The replacement of an asymmetric carbon
(compound 1) group (compound 6d) leads to poor performance
by this molecule.
a/c
a
slightly lower than for 3a and 3b, the transactivation PPAR
and Ki values from binding tests (165% at 7.52 nM) are comparable
to those found for compound 1. Instead of PPAR transactivation
(145% at 9 nM), as a PPAR dual agonist, compound 3c could
be compared to Tesaglitazar.
On the basis of their in vitro results, these three compounds
(3a–c) were investigated in absorption and bioavailability tests
(Table 2).21 With a good percentage of absorption (around 95%),
c
tests
The in vitro values of 8b were comparable to those of compound
1 (Table 1), but the activity observed versus the different parame-
ters tested in vivo was disappointing. The increase in plasma tri-
a
a/c
glycerides suggests that the agonism towards PPARa is not
sufficient to regulate the concentration of fatty acids. Moreover
the increase in body weight (304%) suggests possible inflammatory
effects. The values obtained with compounds 3b and 3c are not
conclusive.
Table 2
In vivo activity of compounds 1 and 6b in ob/ob model
Compound
Absorption (%)
CaCo2
Bioavailability (%)
Human hepatocyte microsomes Rat hepatocyte microsomes
ob/ob mice 4 days (PO 3 mg/kg)
TG
G
Ins
DP
Rosiglitazone
Tesaglitazar
1
3a
3b
3c
8b
100
78
100
95
90
93
21
100
0
47
59
84
27
45
97
0
20
35
32
18
À56
À60
À5
À57
À51
À12
ND
À11
À12
12
À55
À94
À20
ND
0.56
+1.9
À33
ND*
À27
À2
51
0.23
107
304
À2
100
9
À17
TG: triglycerides, G: glycemia, Ins: insulin,
ND not determined
D
P: delta body weight.
*

C. Parmenon et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2683–2687
2687
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Acknowledgments
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17. Gervois, P.; Fruchart, J.-C.; Staels, B. Int. J. Clin. Pract. 2004, 58, 22.
18. a Parmenon, C.; Viaud-Massuard, M.-C.; Guillard, J.; Dacquet, C.; Ktorza, A.;
Caignard, D.-H. WO2006/079719, 2006.; (b) Parmenon, C.; Guillard, J.;
Caignard, D.-H.; Hennuyer, N.; Staels, B.; Audinot-Bouchez, V.; Boutin, J.-A.;
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This work was supported by the French Ministry of Research
and Technology and by Servier Industry: ACI 2202-2005: ‘Mole-
cules and Therapeutics Targets’.
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