Novel non-carboxylic acid retinoids: 1,2,4-Oxadiazol-5-one derivatives

Article abstract of DOI:10.1016/j.bmcl.2008.11.040

We have successfully obtained 1,2,4-oxadiazol-5-one bioisoteres of Am580 or Tazarotene-like retinoids. In particular compound 4 displays an EC₅₀ of 26 nM on RAR-β.

Full text of DOI:10.1016/j.bmcl.2008.11.040

Bioorganic & Medicinal Chemistry Letters 19 (2009) 489–492
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel non-carboxylic acid retinoids: 1,2,4-Oxadiazol-5-one derivatives
Julie Charton a,c,d,e, , Rebecca Deprez-Poulain a,c,d,e, Nathalie Hennuyer b,c,d
Anne Tailleux b,c,d, Bart Staels b,c,d, Benoit Deprez a,c,d,e
,
*
a INSERM U761 Biostructures and Drug Discovery, 3 rue du Professeur Laguesse, Lille F-59006, France
b INSERM U545, Lille F-59019, France
c Faculté de Pharmacie, Université Lille 2, Lille F-59006, France
d Institut Pasteur de Lille, Lille F-59021, France
e PRIM (www.drugdiscovery-lille.org), Lille F-59006, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We have successfully obtained 1,2,4-oxadiazol-5-one bioisoteres of Am580 or Tazarotene-like retinoids.
In particular compound 4 displays an EC50 of 26 nM on RAR-b.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 17 September 2008
Revised 12 November 2008
Accepted 12 November 2008
Available online 18 November 2008
Keywords:
1,2,4-Oxadiazol-5-one
Retinoid
Natural and synthetic retinoids display pleiotropic effects that
have led to their development as therapeutic drugs in a number
of applications including acne, psoriasis and cancer.1 Retinoids
have a remarkable range of activities. Indeed, they regulate embry-
onic development, bone formation, cell differentiation and prolif-
eration, glucose and lipid metabolism, carcinogenesis and
immune function.2–4 The biological activities of retinoids are med-
iated by two types of nuclear receptors, Retinoic Acid Receptors
of retinoids led to loss of activity.9 On the contrary, thiazolidined-
ione moiety has been described by Tashima et al. to be an effective
replacement of the carboxylic acid (Fig. 2a).10,11 More recently, bio-
isosteric replacement of carboxylic acid with a tropolone ring is re-
ported (Fig. 2b).12,13
Another example of acidic heterocycle is the 1,2,4-oxadiazol-5-
one ring, found in AT1 antagonists14, COX inhibitors15, PLA2 inhib-
itors16 and modulators of GluR.17 This heterocycle can replace car-
boxylic acids but displays geometrically different protomers and
slightly different physico-chemical properties. Compounds bearing
this heterocycle have different lipophilic properties that may
translate into improved bioavailability compared with their car-
(RARs or NR1B: RAR
a
, RARb and RARc), and Retinoid X Receptors
(RXRs or NR2B: RXR
a
, RXRb and RXR
c
). At the molecular level
RARs and RXRs form heterodimers. At the cellular level, these
receptors are DNA binding proteins that regulate gene transcrip-
tion in response to ligand-binding. The success of RAR modulation
in the treatment of acute promyelocyticleukaemia (APL)5 has stim-
ulated considerable interest in the development of RAR and RXR
modulators. Most potent retinoids, such as Am580 or Tazarotenic
acid have an aromatic carboxylic acid moiety instead of the poly-
enecarboxylic acid of retinoic acid (ATRA, Fig. 1). In this family,
the hydrophobic part and the linker (X) can be varied with reten-
boxylic analogues. Indeed,
DlogD7.4 between benzoic acid and 3-
phenyl-1,2,4-oxadiazol-5-one = 0.7 log unit, the oxadiazolone
being more hydrophobic than its carboxylic counterpart.18 In our
project aiming at synthesizing various analogues of pharmacolog-
ically active carboxylic acids, we explored the replacement of the
carboxylic acid function by the 1,2,4-oxadiazol-5-one moiety in
two series of retinoids: analogues of the tazarotene, a RAR-b,
c
tion of high activity. Tazarotene, an RAR-b,
c
selective acetylenic
selective acetylenic retinoid, and Am580, an RAR-a selective reti-
retinoid, was chosen for development as a topical agent for psori-
noid (Fig. 3).
asis and acne. Am580 (RAR-
a
selective) has powerful and selective
First, we investigated the synthesis of tazarotenic acid ana-
logues.19 Precursors 1 and 2 were synthesized as previously de-
scribed from the corresponding nitrile in two steps (Scheme 1).20
We have recently reported a strategy for solid-phase synthesis
of acetylenic derivatives of 3-aryl-1,2,4-oxadiazol-5-one thanks
to a Sonogashira reaction.19 Compound 1 was thus grafted on resin
and then reacted with 6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetra-
hydro-naphthalene 3 to yield compounds 4 (Scheme 2).
cyto-differentiating effects on APL.6,7
Various acidic heterocycles are classically used by medicinal
chemists as carboxylic acid bioisosteres.8 Tetrazole is a common
bioisostere of the carboxylic acid group but in the particular case
* Corresponding author. Tel.: +33 (0) 320 964928; fax: +33 (0) 320 964 709.
E-mail address: julie.charton@univ-lille2.fr (J. Charton).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.11.040

490
J. Charton et al. / Bioorg. Med. Chem. Lett. 19 (2009) 489–492
O
Carboxylic Acid Function
or prodrug
OH
X
Y
R
Linker
Hydrophobic Part
O
O
O
O
OH
O
OH
N
N
H
Tazarotene
ATRA (all-trans retinoic acid)
AM580
S
O
R'=
OH
R'
Figure 1. General structure of retinoids and examples.2
O
O
N
O
N
OH
O
O
O
i
N
NH
N
O
H
S
H
N
H
X
O
I
R
R
a
5 : p-A,
6 : m-A
7 : m-B
b
Figure 2. Non-benzoic acid retinoids.
B=
A =
Scheme 3. Reaction conditions: (i) 1 or 2, PdCl2(PPh3)2, CuI, NEt3, DMF, 80 °C, 7 h,
(5: 50%, 6: 83%, 7: 56%).
N
O
N
H
O
Linker
O
R
Hydrophobic Part
O
i,ii
i
O
8
OH
I
Figure 3. Generic structure of the potential retinoid 1,2,4-oxadiazol-5-one
O
derivatives.
O
OH
9
OH
I
O
N
Scheme 4. Reaction conditions: (i) Alkyne (1.2 equiv), PdCl2(PPh3)2 (0.05 equiv),
CuI (0.1 equiv), NEt3, DMF, 80 °C, 5 h, 8a: 52%, 9: 20%, (ii) NaOH (2 equiv), EtOH, 8:
100%.
CN
O
i, ii
N
R
R
H
R = p-I ; m-I
1 R =
p
-I
i,ii
2
R = m-I
O
N
Am580
O
O
N
O
Scheme 1. Reaction conditions: (i) NH2OH.HCl, DIEA, EtOH, reflux, 8 h, (1a: 75%, 2a:
95%). (ii) CDI, DBU, dioxane, 110 °C, 2 h, (1: 80%, 2: 80%).
H
Cl
N
H
iv,v
iii,
10
In the search of a more cost-effective synthesis, we also devel-
oped the first solution Sonogashira coupling with an unprotected
Scheme 5. Reaction conditions: (i) H2N–C6H4–CO2Et, NEt3, THF, rt, 3 h, 85%. (ii)
NaOH, EtOH, H2O, 40 °C, 12 h, 90%. (iii) H2N–C6H4–CN, NEt3, THF, rt, 12 h, 10a: 98%.
(iv) NH2OH.HCl, DIEA, EtOH, reflux, 6 h, 10b: 91%. (v) CDI, DBU, dioxane, 110 °C, 2 h,
10: 44%.
1,2,4-oxadiazol-5-one ring. Such strategy has been used for
21
Suzuki–Miyaura reactions
and successfully applied for the
synthesis of compounds 5–7 (Scheme 3).
O
N
O
O
O
N
I
H
N
H
H
O
Br
O
N
i, ii
iii
3
4
Scheme 2. Reaction conditions: (i) trimethylsilylacetylene (1.3 equiv), PdCl2(PPh3)2 (0.05 equiv), CuI (0.1 equiv), NEt3, 70 °C, 12 h (ii) KOH (0.1 N), Isopropanol, 12 h, rt (iii)
alkyne (10 equiv), PdCl2(PPh3)2 (1.1 equiv), CuI (2.2 equiv), DIEA (30 equiv), DMF, rt, 3 h then 5% TFA/CH2Cl2, rt, 3 h.

J. Charton et al. / Bioorg. Med. Chem. Lett. 19 (2009) 489–492
491
Some carboxylic acid analogues described in literature were
also synthesized like compounds 8 and 9 in order to compare ret-
inoidal activity of our oxadiazolone derivatives with known reti-
noic compounds (Scheme 4).
Am580 and its 1,2,4-oxadiazol-5-one analog 10 were synthe-
sized as described in Scheme 5.
The retinoidal activities of the synthesized compounds were
examined in terms of potency and efficacy and results are pre-
sented in Table 1. Chimeric receptors RAR-Gal4 where RAR li-
gand-binding domain (LBD) fused to the DNA binding domain
(DBD) of the yeast transcription factor GAL4 and reporter gene con-
taining a GAL4 response element–driven luciferase activity have
Table 1
Transcriptional activation assay dataa
Compound
RAR-
a
RAR-b
RAR-c
EC50 (nM)
>1000
Eff (%)
EC50 (nM)
10.0
Eff (%)
35c
EC50 (nM)
10.0
Eff (%)
44c
O
b
8
—
OH
N
O
b
b
5
6
>1000
>1000
—
820.0
34
>1000
>1000
—
N
H
O
N
b
b
b
O
O
—
>1000
—
—
N
H
9
0.6
53
0.3
83
50
0.6
125
48
O
OH
N
N
b
O
4
7
>1000
>1000
—
26.0
91.0
O
H
N
O
b
b
b
—
>1000
—
>1000
—
N
H
O
O
OH
O
O
Am580
0.3
43
40
8.6
46
13.0
43
N
H
O
N
O
N
b
b
H
10
520.0
>1000
—
>1000
—
N
H
O
O
Tazarotene
63.0
17.0
54
0.8
57
40.0
0.2
72
N
S
O
ATRA
100
12.0
100
100
OH
a
The data are expressed as averages of % efficacy and EC50. Eff.: efficacy is relative to ATRA defined as 100%.
b
c
<10% at 10
lM.
Efficacy is relative to Tazarotene defined as 100%.

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J. Charton et al. / Bioorg. Med. Chem. Lett. 19 (2009) 489–492
been transiently transfected. Mammalian cells did not contain GAL,
only the transfected RAR-GAL4 chimeric receptors can activate the
reporter gene, eliminating interference from endogenous nuclear
receptors.22
References and notes
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Habich, N.; Huet, J.; Redeuilh, C.; Ombetta, J.-E.; Godfroid, J.-J. Bioorg. Med.
Chem. 2005, 13, 1989.
17. Valgeirsson, J.; Nielsen, E. O.; Peters, D.; Mathiesen, C.; Kristensen, A. S.;
Madsen, U. J. Med. Chem. 2004, 47, 6948.
Tazarotene and its analogue 8 are RAR-b,c selective acetylenic
retinoids, whereas analogue 9 is very active on the three subtypes.
Interestingly, 1,2,4-oxadiazol-5-one 4 and 5 activities differ from
their carboxylic acids analogues. Indeed, compound 5 is slightly ac-
tive on RAR-b. Compound 4, though nanomolar on RAR-b
(EC50 = 26 nM), is less active than 9 but displays a better selectivity
on RAR-b,csubtypes and an efficacy comparable with tazarotene. As
expected, bended analogue 7 is not active since it is not linear en-
ough to fit the RAR pharmacophore. In the second series, compound
10 is active on RAR-a with a similar efficacy to that of Am580 (40
versus 43%). In the light of these results, both compounds 4 and
10 could be good starting points for further optimization.
All these compounds were checked for cross-reactivity with the
retinoid X receptor (RXR a, b, c) and found to be inactive.
In conclusion, we have described the solid-phase or solution-
phase syntheses of a new series of non-carboxylic acid RAR ligands.
We have shown that the 1,2,4-oxadiazol-5-one moiety can act as a
bioisostere of the carboxylic acid function in retinoid structures. In
particular the retinoidal activity of compound 4 (RAR-b,c selective)
is significant, considering that replacement of the carboxylic acid
in retinoid structures with bioisosteric functional groups is gener-
ally ineffective. These non-carboxylic acid type RAR ligands may
exhibit different pharmacological behaviors from classical carbox-
ylic acid compounds, as well as unique biological activity, and they
may provide further scope for clinical applications.
18. Measured with shake-flash method, UV detection.
19. U.S. Patent 5,349,105, Allergan, issued 20th September 1994.
20. Charton, J.; Cousaert, N.; Bochu, C.; Willand, N.; Deprez, B.; Deprez-Poulain, R.
Tetrahedron Lett. 2007, 48, 1479.
21. Stansfield, I.; Pompei, M.; Conte, I.; Ercolani, C.; Migliaccio, G.; Jairaj, M.;
Giuliano, C.; Rowley, M.; Narjes, F. Bioorg. Med. Chem. Lett. 2007, 17,
5143.
Acknowledgments
22. Cell culture. Cos-7 cells were obtained from ATCC (CRL-1651). Cells were
maintained in standard culture conditions (Dulbecco’s modified Eagle’s
minimal essential medium supplemented with 10% fetal calf serum at 37 °C
in a humidified atmosphere of 5% CO2/95% air). Medium was changed every 2
days.Effect of compounds on RARs transcriptional activity using chimaeric
protein constructs.Cos-7 cells were seeded in 60 mm dishes in DMEM
supplemented with 10% FCS and incubated at 37 °C for 16 h prior
transfection. Cells were transfected in DMEM 10% FCS, using jetPEITM
transfection reagent, with reporter (pGal5-TK-pGl3) and expression plasmids
We are grateful to the Institutions that support our laboratory
(Inserm, Université de Lille2 and Institut Pasteur de Lille). Data
management was performed using Pipeline PilotTM from Scitegic.
We thank also the following Institutions or companies: CAMPLP
and VARIAN.inc. This project was supported by the Fondation pour
la Recherche Medicale (FRM) - Nord-Pas-de-Calais.
(pGal4-hRARa, cor b). Cells were incubated at 37 °C. After 24 h, cells were
trypsinised and seeded in 96-well plates and incubated for 6 h in DMEM
containing 0.2% FCS. Cells were then incubated 16h in DMEM 0.2% FCS and
increasing concentrations of the compounds tested or vehicle (DMSO). At the
end of the experiments, cells were washed once with PBS and the luciferase
and the b-galactosidase assays were performed.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.11.040.