Syntheses and evaluation of naphthalenyl- and chromenyl-pyrrol-benzoic acids as potent and selective retinoic acid receptor α agonists

Article abstract of DOI:10.1016/S0960-894X(00)00067-6

Synthesis and structure-activity relationships (SAR) of RARα-selective agonists are discussed. 4-[5-(5,8-Dimethyl-2H-3-chromenyl)-1H-2-pyrrolyl]benzo ic acid (12a), which possesses a flat structural moiety and an oxygen atom at the hydrophobic part, showed highly selective transactivation activity at the RARα receptor. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00067-6

Bioorganic & Medicinal Chemistry Letters 10 (2000) 623±625
Syntheses and Evaluation of Naphthalenyl- and Chromenyl-
pyrrolyl-benzoic Acids as Potent and Selective Retinoic Acid
Receptor ꢀ Agonists
Shigeki Hibi,* Katsuya Tagami, Kouichi Kikuchi, Hiroyuki Yoshimura, Kenji Tai,
Takayuki Hida, Naoki Tokuhara, Toshihiko Yamauchi and Mitsuo Nagai
Tsukuba Basic Research Laboratories, Eisai Co., Ltd., 1-3, Tokodai 5-chome, Tsukuba-shi, Ibaraki, 300-2635, Japan
Received 16 December 1999; accepted 20 January 2000
AbstractÐSynthesis and structure±activity relationships (SAR) of RARa-selective agonists are discussed. 4-[5-(5,8-Dimethyl-2H-3-
chromenyl)-1H-2-pyrrolyl]benzoic acid (12a), which possesses a ¯at structural moiety and an oxygen atom at the hydrophobic part,
showed highly selective transactivation activity at the RARa receptor. # 2000 Elsevier Science Ltd. All rights reserved.
Retinoids, natural and synthetic analogues of all-trans
retinoic acid (ATRA), have a variety of potent biologi-
cal activities, including induction of cellular prolifera-
tion, di€erentiation and death, as well as developmental
changes.1 There are three distinct receptor subtypes
(RARa, b and g), which possess considerable homology
in their ligand-binding domains. RARs elicit their gene
transcriptional activity in the form of heterodimers with
retinoid X receptors (RXRs).2 We have focused our
attention on RARa agonists, because selective RARa
agonists seem to be promising compounds for the
treatment of dermatological diseases and immunologi-
cal disorders, as described in the preceding paper.3
reported as an RARa-selective agonist (Chart 1). Here,
we discuss the syntheses and SAR of retinoids which
possesses a ¯at moiety, such as naphthalene and benzo-
pyran, at the hydrophobic part.
Chemistry
Naphthalenyl and benzopyranyl-pyrrolyl derivatives (11
and 12) were synthesized by the method of Scheme 1.
The carbaldehydes (4 and 5), which were prepared by
the reported method,4b were treated with vinyl Grignard
reagent and oxidized with manganese(IV) oxide (acti-
vated) to a€ord enone derivatives (6 and 7). The enone
derivatives (6 and 7) were coupled with methyl 4-for-
mylbenzoate (8) to give the diketones (9 and 10). These
derivatives (9 and 10) were treated with ammonium
acetate to a€ord the corresponding pyrrole derivatives,
which were hydrolyzed to the ¯at moiety-pyrrole-ben-
zoic acid derivatives (11 and 12).
In the course of our research directed towards RAR
agonists and antagonists,4 we have introduced various
novel moieties into the hydrophobic part of retinoids.
We found that a naphthalenyl-triene derivative (1;
ER-329065) showed more selective binding anity and
transactivation activity for RARa than a 1,2,3,4-tetra-
hydro-1,1,4,4-tetramethylnaphthalenyl-triene derivative
(2; Ro 13-63076), which has a bulky moiety at the
hydrophobic part (Chart 1, Table 1). Based on these
results, we planned to introduce a ¯at moiety, such as
naphthalene or benzopyran, into the hydrophobic part
of ligands, with a 2,5-disubstituted pyrrole as the linker
part. Such novel retinoids might be more selective for
RARa than compound 3 (ER-346174d), which has been
Results and Discussion
The subtype-selective competitive binding and transac-
tivation data are summarized in Table 1. The 5,8-di-
methylnaphthalene derivative 11a did not show anity
for RARb or RARg, whereas it has moderate binding
anity for RARa. This compound (11a) is 3-fold less
potent at RARa than ATRA, but was 250 and 2000-
fold less potent at RARb and RARg, respectively. The
mono 8-methyl derivative (11b) is less potent than the
*Corresponding author. Tel.: +81-298-47-5863; fax: +81-298-47-
2037; e-mail: s-hibi@hhc.eisai.co.jp
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00067-6

624
S. Hibi et al. / Bioorg. Med. Chem. Lett. 10 (2000) 623±625
Chart 1.
Table 1. Competitive binding and transactivation data for retinoids
Binding anitya
Subtype-speci®c transactivatione
b
f
Relative IC50
Relative EC30
Compound
R1
R2
R3
R4
RARa
RARb
RARg
RARa
2.8
49
90
Ðg
Ðg
1.1
1.8
4.5
RARb
RARg
11a
11b
11c
11d
11e
11f
12a
12b
1
Me
Me
H
Me
Ph
i-Pr
Me
Me
H
H
Me
Me
H
H
H
H
H
H
H
Me
H
H
Me
H
Me
Me
H
H
Me
H
24
15
Ðc
Ðc
Ðc
Ðc
Ðc
Ðc
Ðc
Ðc
49
Ðc
Ðc
Ðc
Ðc
Ðc
910
Ðc
Ðc
227
250
Ðg
Ðg
Ðg
880
78
240
1030
11
2200
Ðg
Ðc
Ðc
1.4
<1.0
9.7
50
Ðg
Ðg
Ðg
88
H
H
3600
5250
660
2.7
20
2
0.49
0.34
0.67
0.27
0.20
0.24
ATRAh
1.0
0.89 nMd
1.0
0.94 nMd
1.0
0.62 nMd
1.0
1.10 nMh
1.0
0.69 nMh
1.0
0.18 nMh
aSpeci®c binding anity was de®ned as the total binding minus the nonspeci®c binding, and the 50% inhibitory dose (IC50) values were obtained
from logarithmic plots. In some cases, Scatchard plot analysis was performed. The selectivity of test compounds for each receptor is indicated as
relative IC50, where the IC50 value for each receptor was divided by that of the natural ligand (ATRA).
bIC50/ATRA IC50
c Ð: not detectable (relative IC50 >1000).
dATRA IC50
.
.
eEC30 values were determined from full dose±response curves ranging from 0.1 nM to 3.0 mM. Retinoid activity is expressed in terms of relative
EC30, which is the concentration of retinoid required to produce 30% of the maximal observed response, normalized relative to that of ATRA.
fEC30/ATRA EC30
.
g Ð: not detectable (relative EC30 >10,000).
hATRA EC30
.
5,8-dimethylnaphthalene derivative (11a) in transactiva-
tion activity for RARa. The 5,7-dimethyl naphthalene
derivative (11c) did not bind to any of the RARs, and
showed 90-fold less RARa-agonistic activity than
ATRA. The 5,6,7,8-tetramethylnaphthalene derivative
(11d) had no anity or transactivation potency for
RARs.
8-phenylnaphthalene derivative (11e) showed RARa
binding anity comparable to that of ATRA, it did not
bind to any other receptor, or activate RARs. The 8-
isopropylnaphthalene derivative (11f) possessed stron-
ger binding anity than ATRA at RARa, and did not
show selectivity for RARa transactivation.
We introduced an oxygen atom into the hydrophobic
part of the retinoid structure to obtain more polar reti-
noids which might show improved pharmacokinetic
characteristics. The benzopyran derivatives (12), which
These results suggest that methyl group at positions 5
and 8 speci®cally enhance RARa transactivation, while
those at positions 6 and 7 are unfavorable. Although the

S. Hibi et al. / Bioorg. Med. Chem. Lett. 10 (2000) 623±625
625
Scheme 1. Reagents and conditions: (a) vinylmagnesium bromide, THF, rt, 1±2 h; (b) MnO2, CH2Cl2, rt, 12 h; 13±53% (for a and b); (c) 3-benzyl-5-
(2-hydroxyethyl)-4-methylthiazolium chloride, CH3CO2Na, EtOH, re¯ux, 1±2 h; 15±82%; (d) CH3CO2NH4, MeOH, re¯ux, 3±5 h; 52±95%;
(e±i) NaOH aq. EtOH, re¯ux, 1 h; (e-ii) dil. HCl; 68±95%.
have an oxygen-containing ¯at structural moiety, both
showed signi®cant selectivity in transactivation activity
for RARa, through 12b is less potent than the dimethyl
benzopyranyl derivative (12a).
potent and e€ective RARa agonist, and could be a lead
compound for development of clinically useful RARa
agonists.
HL-60 di€erentiation activity was measured for 11a±f
and 12a,b, using CD11b as a marker of di€erentiation.
Only the 8-isopropyl-naphthalenyl-pyrrole derivative
(11f) showed moderate potency (100 nM; ED30); the
other compounds had no detectable activity. We also
studied transactivation activity for RXRa, but these
compounds (11a±f and 12a,b) did not show transacti-
vation activity (data not shown).
References and Notes
1. Mangelsdorf, D. J.; Umesono, K.; Evans, R. M. In The
Retinoids; Sporn, M. B.; Roberts, A. B.; Goodman, D. S.,
Eds; Raven Press: New York, 1994.
2. Leid, M.; Kastner, P.; Chambon, P. Trends Biochem. Sci.
1992, 17, 427 and references cited therein.
3. Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tai, K.; Hida, T.;
Tokuhara, N.; Ishibashi, A.; Yamauchi, T.; Nagai, M. Bioorg.
Med. Chem. Lett. 2000, 10, 619.
In conclusion, a ¯at structural moiety, such as naph-
thalene and benzopyran, in the hydrophobic part of
retinoids seems to be essential for selective RARa
transactivation activity. Methyl substituents at positions
5 and 8 are important for RARa selectivity in the
naphthalenyl-pyrrole derivatives (11) and the benzo-
pyranyl-pyrrole derivatives (12). Furthermore, one of
the naphthalenyl-pyrrole derivatives (11a; ER-35368)
and the benzopyranyl-pyrrole derivatives (12a; ER-
41666) possess signi®cant selectivity for the RARa
receptor. These selective RARa agonists are potential
therapeutic agents for diseases where RARa is patho-
genically deactivated. 4-[5-(5,8-Dimethyl-2H-3-chrome-
nyl)-1H-2-pyrrolyl]benzoic acid (12a) is a particularly
4. (a) Yoshimura, H.; Agai, M.; Hibi, S.; Kikuchi, K.; Abe, S.;
Hida, T.; Higashi, S.; Hishinuma, I.; Yamanaka, T. J. Med.
Chem. 1995, 38, 3163. (b) Tagami, K.; Yoshimura, H.; Nagai,
M.; Hibi, S.; Kikuchi, K.; Satoh, T.; Okita, M.; Okamoto, Y.;
Nagasaka, Y.; Kobayashi, N.; Hida, T.; Tai. K.; Tokuhara,
N.; Kobayashi, S. WO97/34869. (c) Hibi, S.; Kikuchi, K.;
Yoshimura, H.; Nagai, M.; Tai, K.; Hida, T. J. Med. Chem.
1998, 41, 3245. (d) Kikuchi, K.; Hibi, S.; Yoshimura, H.;
Tokuhara, N.; Tai, K.; Hida, T.; Yamauchi, T.; Nagai, M. J.
Med. Chem. 2000, 43, 409.
5. Compound 1 (ER-32906) was synthesized by employing
usual retinoid chemistry as reported for the synthesis of RXR
agonists6 from 4a (overall yield 33%).
6. Loeliger, P.; Bollag, W.; Mayer, H. Eur. J. Med. Chem.
1980, 15, 9.