Synthesis and evaluation of arylalkoxy- and biarylalkoxy-phenylamide and phenylimidazoles as potent and selective sphingosine-1-phosphate receptor subtype-1 agonists

Article abstract of DOI:10.1016/j.bmcl.2009.02.073

In pursuit of potent and selective sphingosine-1-phosphate receptor agonists, we have utilized previously reported phenylamide and phenylimidazole scaffolds to explore extensive side-chain modifications to generate new molecular entities. A number of desi

Full text of DOI:10.1016/j.bmcl.2009.02.073

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2315–2319
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of arylalkoxy- and biarylalkoxy-phenylamide and
phenylimidazoles as potent and selective sphingosine-1-phosphate receptor
subtype-1 agonists
a
b
a
b
Ghotas Evindar a, , Alexander L. Satz , Sylvie G. Bernier , Malcolm J. Kavarana , Elisabeth Doyle ,
Jeanine Lorusso b, Nazbeh Taghizadeh b, Keith Halley b, Amy Hutchings b, Michael S. Kelley a,
Albion D. Wright b, Ashis K. Saha a, Gerhard Hannig b, Barry A. Morgan a, William F. Westlin b
*
a Department of Medicinal Chemistry, Praecis Pharmaceuticals Incorporated, 830 Winter Street, Waltham, MA 02451, United States
b Department of Preclinical Research, Praecis Pharmaceuticals Incorporated, 830 Winter Street, Waltham, MA 02451, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
In pursuit of potent and selective sphingosine-1-phosphate receptor agonists, we have utilized previously
reported phenylamide and phenylimidazole scaffolds to explore extensive side-chain modifications to
generate new molecular entities. A number of designed molecules demonstrate good selectivity and
excellent in vitro and in vivo potency in both mouse and rat models. Oral administration of the lead mol-
ecule 11c (PPI-4667) demonstrated potent and dose-responsive lymphopenia.
Received 10 December 2008
Revised 17 February 2009
Accepted 19 February 2009
Available online 23 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
S1P
S1P1 agonist
EDG1
Lymphopenia
FTY-720
Sphingosine-1-phosphate
Arylalkoxy-phenylamide
Arylalkoxy-phenylimidazoles
Biarylalkoxy-phenylamide
Biarylalkoxyphenylimidazoles
Sphingosine-1-phosphate (S1P) receptors, a class of G-protein
coupled receptors (GPCRs), are important molecular receptors for
drug discovery and development because of the significant role
they play in a diversity of physiological and pathophysiological
processes.1 Activation or antagonism of members of this cluster
of five receptors (S1P1–5) with the natural ligand S1P can induce
various effects on cardiovascular and immune system function
and other yet poorly defined effects on additional physiological
systems including pulmonary function.1
FTY-720 phosphate, a potent non-selective S1P receptor ago-
nist, has profound immunomodulatory activity through alteration
of lymphocyte trafficking.2 This activity is due to activation of
S1P receptor subtype 1 (S1P1) signaling cascades. In contrast, ago-
nists of S1P receptor subtype 3 (S1P3) have been associated with
negative chronotropic effects in preclinical studies which may
translate into clinical side effects including bradycardia.3 We re-
cently reported two classes of S1P receptor agonists with excellent
potency at the S1P1 receptor with good oral activity (Scheme 1).4 In
order to retain the positive therapeutic properties while further
reducing the potential for side effects of non-selective S1P receptor
agonists like FTY-720, we have explored structural modifications to
OH
H2N
OH
FTY-720
PPI-4621
C8H17
H2N
O
H
N
Me
OH
C8H17
O
O
NH2
NH
N
Me
OH
PPI-4691
C8H17
* Corresponding author. Tel.: +1 781 795 4423.
E-mail address: ghotas.x.evindar@gsk.com (G. Evindar).
Scheme 1.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.02.073

2316
G. Evindar et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2315–2319
these scaffolds to further improve the agonist selectivity for S1P
receptor subtype 1 over 3. In the design of potent sphingosine-1-
phosphate receptor agonists in the phenylamide and phenylimida-
zole scaffolds, we reported two potent lead molecules, PPI-4621
and PPI-4691 (Scheme 1), with moderate selectivity for S1P1 versus
S1P3 and significant in vivo activity in mouse.4
To further improve agonist selectivity for S1P1 over S1P3, we ex-
plored extensive tail modifications and developed a robust struc-
tural–activity relationship (SAR) in the phenylamide scaffold
series (Fig. 1). The initial effort was focused on carbocycle and het-
erocycle insertion (Q) in the tail region of PPI-4621, where X can be
an inserted linker, and developed an early SAR to access potent or-
ally active molecules using in vivo lymphopenia as the biological
endpoint.
One general approach for the synthesis of the desired agonists is
described in Scheme 2. Nucleophilic substitution of the desired
alcohol5 on 1-fluoro-4-nitrobenzene (1, Z = F) in the presence of
base afforded nitrobenzene 2. An alternative approach to synthesis
of nitrobenzene 2 was through Mitsunobu reaction of 4-nitrophe-
nol (1, Z = OH) with the desired alcohol.
Hydrogenation of the nitro group followed by peptidic coupling
of the aniline with (S)-2-tert-butoxycarbonylamino-3-hydroxy-2-
methyl-propionic acid using either N-ethyl-N0-(3-dimethylamino-
propyl)carbodiimide (EDC), 1-hydroxybenzotriazole (HOBt), and
N,N-diisopropylethylamine (DIPEA) or O-(7-azabenzotriazol-1-yl)-
1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and
DIPEA afforded protected amino-alcohols 3. An alternative approach
to synthesis of 3a–3o was through HATU coupling of (S)-2-tert-
butoxycarbonylamino-3-hydroxy-2-methyl-propionic acid with
4-aminophenol followed by copper(II)-promoted coupling of vari-
ous arylboronic acids with the phenol to generate biaryl-ether de-
sired products. Removal of the Boc protecting group with
trifluoroacetic acid (TFA) afforded final compound 4.
A set of designed molecules are reported in Table 1. These ami-
no-alcohols were orally administered to determine their in vivo
activity by measuring redistribution of circulating lymphocytes
in the mouse 6 h after administration of the compounds. When
the tail was modified to a phenyl group or phenyl group substi-
tuted at positions 4- and/or 3- with an electron conductive halo-
gen, an electron withdrawing group, or an electron rich alkyl or
alkoxyl, no lymphopenia was observed (compounds 4a–4e and
4g–4o). However, the 4-biphenyl tail provided significant lympho-
penia. When the X was changed from O to CH2CH2O little or no
change in absolute lymphocyte count was observed regardless of
the substitution on the phenyl group (Q) or when a naphthyl group
was utilized (compounds 4p–4v). Change of the R-Q group to a 4-
biaryl system provided good to excellent activity especially when R
NO2
NO2
i
ii, iii
Me
Q
R
iv
X
Z
2
1
Z = F or OH
Boc
NH
H2N
O
H
N
H
Me
N
OH
OH
Q
O
Q
R
X
R
X
3
4
v, vi
NH2
HO
Scheme 2. Reagents and conditions: (i) alcohol, NaH or KOtBu, THF, 60–70 °C, or
alcohol, PPh3, diethylazodicarboxylate, CH2Cl2; (ii) H2, 10% Pd/C, MeOH or N2H4,
10% Pd/C, EtOH, 80 °C; (iii) (S)-2-tert-butoxycarbonylamino-3-hydroxy-2-methyl-
propionic acid, EDC and HOBt or HATU, DIPEA, DMF or CH2Cl2; (iv) TFA, CH2Cl2; (v)
(S)-2-tert-butoxycarbonylamino-3-hydroxy-2-methyl-propionic acid, HATU, DIPEA,
DMF; (vi) ArB(OH)2, Cu(OAc)2, molecular sieves, pyridine, CH2Cl2.
was unsubstituted phenyl or contained small-sized substitutions
regardless of the electronic character (4w–4ae). When 3-biphenyl
was used in place of 4-biphenyl the compound lost activity (4af).
Heteroaromatic substitution at R was also well tolerated (4ag–
4ak). When the X group was modified to C4 and C5 ethers, moder-
ate to excellent in vivo activity was observed with R-Q being a sim-
ple aryl or cyclohexyl group.
In another series of tail modifications, we chose to explore the
invention of a substituted phenyl system without the ether con-
nection. The compounds were synthesized as described in Scheme
3. Suzuki cross-coupling of the boronic acid 6 with 4-bromoaniline
5 provided 4-biphenylamino 7.6 4-Biphenylamino 7 was then cou-
pled with (R)-2-tert-butoxycarbonylamino-3-hydroxy-2-methyl-
propionic acid treated with TFA to generate the final compound
9. The in vivo biological activity is reported in Table 2. When R
was a para-substituted Me or Et little or no reduction in circulating
lymphocyte count was observed (9a and 9b). meta-Substitution
with an alkyloxy group gave a similar result to 9a and 9b regard-
less of the nature of the alkyl group. The 3,4-methylenedioxy group
(9g) demonstrated the greatest lymphopenia, 40%, in this series.
Therefore, regardless of the R substitution on the phenyl group,
low to moderate lymphopenia was induced by this series of
molecules.
In order to determine the agonist binding activity for both S1P1
and S1P3, we selected several amino-alcohols based on the abso-
lute in vivo lymphocyte reduction and synthesized the correspond-
ing phosphates. These were synthesized through two different
approaches as reported in Scheme 4. In the first approach, the reac-
tion of free amine or Boc-protected amino-alcohol with excess
diethyl chlorophosphate in the presence of triethylamine afforded
phospho-triester 10. The phopho-triester 10 was then treated with
excess bromotrimethylsilane to give the final phosphate 11 after
preparative HPLC purification. An alternative approach for phos-
phate synthesis was through synthesis of the intermediate di-
tert-butyl phosphate using di-tert-butyl diisopropylphosphorami-
dite and 1H-tetrazole followed by oxidation to phosphate ester
and removal of the tert-butyl groups by a method analogous to that
reported by Clemens and co- workers.7 S1P and synthetic phos-
phate agonist binding activities were measured using a [33P]S1P
receptor binding assay according to an earlier report (Table 3).4
In the 4-biphenyl system when X was O, the agonist showed low
head-piece
H2N
linker
tail
H
N
Me
OH
O
O
X
PPI-4621
H2N
O
H
N
Me
OH
Q
R
Figure 1. General approach for tail modification in PPI-4621.

G. Evindar et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2315–2319
2317
Table 1
Table 2
Percent lymphopenia obtained upon 10 mg/kg oral (PO) administration of the alcohol
Percent lymphopenia obtained upon 10 mg/kg oral (PO) administration of the alcohol
H2N
H2N
N
H
H
Me
Me
N
OH
OH
Q
O
O
R
X
R
Agonist
R
Q
X
%La
Agonist
R
%La
4a
H
Ph
O
N
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
H
4-Me
4-Et
4-nBu
N
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4-F
4-Cl
4-Et
4-nBu
4-Ph
4-OnBu
3-CF3
3-iPr
3-OMe
3-OEt
3-OnPr
3-OiPr
3-OnBu
3-OBn
4-OMe
4-OEt
4-Cl
3,4-diCl
4-CF3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
10
81
N
N
N
N
N
33
N
N
10
N
N
N
10
N
18
29
N
N
N
40
22
34
15
20
23
16
31
4-OMe
4-OnBu
3,4-Methylenedioxy
3-iPr
3-OMe
3-OEt
3-OnPr
3-OiPr
3-OnBu
3-OBn
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2CH2O
CH2(CH2)3O
CH2(CH2)4O
CH2(CH2)3O
CH2(CH2)3O
CH2(CH2)3O
N = negligible.
a
%L = Lymphopenia (percent decrease in circulating lymphocytes compared to
time-matched vehicle control).
4t
4u
4v
4w
4x
4y
3-CF3
H
4-Ph
N
N
81
10
N
OH
B
NH2
NH2
i
40-OEt-4-Ph
40-Et-4-Ph
40-iPr-4-Ph
40-Cl-4-Ph
30-CF3-4-Ph
20-Me-4-Ph
20-Cl-4-Ph
20-CN-4-Ph
3-Ph
OH
R
+
Br
R
4z
N
N
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
4aj
4ak
4al
4am
4an
4ao
4ap
5
6
7
51
79
75
78
N
78
60
78
68
62
85
64
60
66
74
Boc
H
N
NH
Me
H2N
H
Me
OH
OH
ii
N
iii
O
O
4-(4-Pyridinyl)
4-(3-Pyridinyl)
4-(2-Thiophenyl)
4-(3-Furanyl)
4-(3,5-Dimethylisoxazol-4-yl)
H
R
R
Ph
Ph
Ph
Ph
Ph
Ph
Ph
8
9
Scheme 3. Reagents and conditions: (i) 10% Pd/C, tetrabutyl ammonium chloride
(TBAC), Na2CO3, DMF/H2O, microwaved 10–60 min, 60–120 °C; (ii) (S)-2-tert-
butoxycarbonylamino-3-hydroxy-2-methyl-propionic acid, HATU, DIPEA, CH2Cl2;
(iii) TFA, CH2Cl2.
H
4-OMe
H
H
2-Thiophenyl
c-Hexyl
strated good to excellent binding activity at S1P receptor subtype
4 (S1P4) with the exception of 11a. Compound 11c not only
showed good selectivity for receptor subtype 1 over 3, it also
showed similar selectivity for S1P1 over S1P5 as well.
N = negligible.
a
%L = Lymphopenia (percent decrease in circulating lymphocytes compared to
time-matched vehicle control).
The 4-biphenyl group appeared to be important in both recep-
tor selectivity (11c) and in vivo bioactivity (4w). Further modifica-
tions were made to explore the linker length between the ether
and 4-biphenyl group to potentially improve the agonist binding
activity and selectivity for S1P1 over S1P3 (Table 4). When n was
2 (11o), the agonist maintained similar binding activity with re-
duced selectivity and in vivo activity with respect to the lead mol-
ecule 11c (PPI-4667). However, when n was either 0 or 3, all three
parameters (potency, selectivity, in vivo activity) were reduced sig-
nificantly (11n and 11p). All the agonists in this series (11c and
11n, 11o, and 11p) had potent activity on S1P4 with reduced activ-
ity at the S1P5.
Modification of the amide linker region to a rigid imidazole ring
is reported in Scheme 5 and Table 5. Nucleophilic substitution of
the desired alcohol on 4-fluoroacetophenone (13) afforded the
ether-acetophenone 14. The ether-acetophenone 14 was then con-
verted to the bromo-acetophenone using CuBr2. Reaction of the
bromo-acetophenone with (S)-2-tert-butoxycarbonylamino-3-hy-
droxy-2-methyl-propionic acid gave the intermediate ester which
binding activity at both human receptors S1P1 and S1P3 with little
selectivity (11a). The naphthyl group with X being an ethyl ether
group also had low binding activity at both receptors (11b). How-
ever, the 4-biphenyl group with X being ethyl ether showed sub-
stantial improvement over the X = O counterpart in both S1P1
binding activity and receptor selectivity (11c). Distortion of the
coplanar structure of the two phenyl rings in the 4-biphenyl sys-
tem with ortho-substitution was pursued (11d–11f). The 2-Cl
(11e) substitution performed better than the 2-Me (11d) and 2-
CN (11f) counterparts by increasing the binding activity at S1P1
and maintaining similar selectivity as the corresponding 4-biphe-
nyl analog (11c). Changing the phenyl position in the biphenyl sys-
tem from 4- to 3- was detrimental to S1P1 binding activity (11g).
The 4-(2-thiophyl)phenyl analog showed relatively lower activity
at S1P1 with respect to the corresponding 4-biphenyl analog. Elon-
gation of the X group to 5 and 6 atoms showed a good range of
activities at S1P1 except with lower selectivity for S1P1 over S1P3
(11i–11m). In general, the agonists evaluated (11a–m) demon-

2318
G. Evindar et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2315–2319
Table 3
[
33P]S1P binding activity on human S1P1 and S1P3–5 receptor subtypes
H2N
O
H
N
Me
O
O
P
OH
HO
Q
R
X
Agonist
R
Q
X
hS1P1 IC50 (nM)
hS1P3 IC50 (nM)
hS1P4 IC50 (nM)
hS1P5 IC50 (nM)
S1P3/S1P1
S1P
11a
11b
11c
11d
11e
11f
11g
11h
11i
—
4-Ph
H
—
Ph
Naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
—
O
0.78
186
220
1.05
0.78
0.84
12
2000
21
2.1
0.92
628
2500
200
50
160
1040
10000
3750
100
0.36
100
1.04
123
nd
4.17
nd
nd
nd
nd
nd
10.3
3.6
nd
nd
8.3
2.0
455
nd
122
nd
nd
nd
nd
nd
43.6
2.9
nd
nd
26.2
—
3.3
11
190
64
190
87
5
178
48
1.7
21
4
C2H4O
C2H4O
C2H4O
C2H4O
C2H4O
C2H4O
C2H4O
C4H8O
C5H10
C4H8O
C4H8O
C4H8O
4-Ph
20-Me-4-Ph
20-Cl-4-Ph
20-CN-4-Ph
3-Ph
4-(2-Thiophenyl)
H
H
4-OMe
H
H
11j
11k
11l
O
0.21
4.75
30
2-Thiophenyl
c-Hexyl
120
31.3
11m
1.2
25
nd = not determined.
Table 4
[
33P]S1P binding activity on human S1P1 and S1P3–5 receptor subtypes
H2N
H
N
Me
O
OH
O
P
HO
O
O
n
Agonist
n
hS1P1 IC50 (nM)
hS1P3 IC50 (nM)
hS1P4 IC50 (nM)
hS1P5 IC50 (nM)
S1P3/S1P1
%La
11c
11n
11o
11p
1
0
2
3
1.05
2.5
0.9
200
4.17
6.15
5.24
24.8
122
104
70.4
99.8
190
8.4
61
81
28
61
39
21.1
27.1
10.2
6.9
1.5
a
%L = Lymphopenia (percent decrease in circulating lymphocytes compared to time-matched vehicle control after 6 h upon 10 mg/kg oral (PO) administration of the
corresponding alcohol.
The imidazole analog of 11c (PPI-4667) is 11q which showed a
good overall profile but with relatively reduced binding activity
Approach A:
R'
R'
H2N
R
and selectivity in vitro and less potent in vivo activity on lympho-
penia when the corresponding alcohol was administered orally.
However, decreasing the length of the ethylene section of R to a
methylene generated a more potent agonist 11r with similar selec-
tivity to 11q. Two other analogs in which R was either phenyl-
butylene (11s) or phenyl-pentylene (11t) showed excellent lym-
phocyte reduction, with 11t demonstrating a relative improvement
in binding activity with respect to lead molecule 11c (PPI-4667)
and its corresponding imidazole analog 11q. The imidazole series
did not generate any agonists with overall improvement in profile
over 11c (PPI-4667), but it demonstrated once again the potential
for transferring the SAR information from the phenylamide series
to the phenylimidazole series with relatively reduced selectivity
for S1P1 over S1P3.
NH
Me
NH
Me
ii
i
Me
O
OH
O
OEt
O
O
OH
P
R
R
P
HO
EtO
10
R' = H or Boc
Approach B:
11
Boc
R
Boc
R
NH
Me
t BuO OtBu
H2N
R
NH
Me
i, ii
iii
Me
O
O
OH
O
O
HO
OH
P
P
12
11
A [35S]GTP S functional assay8 was used to further characterize
c
Scheme 4. Reagents and conditions: Appraoch A: (i) excess diethyl phosphorochl-
oridate, Et3N, CH2Cl2, rt, 12–18 h; (ii) excess TMSBr, CH2Cl2, rt, 4–10 h; Approach B:
(i) di-tert-butyl diisopropylphosphoramidite, 1H-tetrazole, THF or THF/CH2Cl2 (1:1),
rt, 2–12 h; (ii) excess H2O2, rt, 1–6 h; (iii) TFA/CH2Cl2 (1:3 v/v), rt, 1–3 h.
the agonist potency and selectivity for S1P1 over S1P3 (Table 6). The
lead molecule 11c showed excellent potency at S1P1 and a high de-
gree of selectivity for S1P1 over S1P3. The biphenyl ether analog 11a
had marginal potency at S1P1. Elongation of X from C2 to C3 and C4
decreased the receptor subtype 1 potency as well as agonist selec-
tivity. Increased flexibility in the tail region either decreased the
agonist potency (11i) or the selectivity (11j and 11m). The imidaz-
was then converted to the imidazole precursor 16 using AcONH4.
Deprotection of the Boc group provided the amino-alcohol 17
(see Scheme 5).

G. Evindar et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2315–2319
2319
Table 5
[
12
33P]S1P binding activity on human S1P1 and S1P3–5 receptor subtypes
10
8
O
R
NH2
N
NH
6
Me
O
HO
O
4
P
OH
2
Agonist
R
hS1P1
IC50
hS1P3
IC50
hS1P4
IC50
hS1P5
IC50
S1P3/ %La
S1P1
0
Vehicle
0.3 mg/kg 1.0 mg/kg 3.0 mg/kg 10.0 mg/kg
PPI-4667 (11c)
(nM)
(nM)
(nM)
(nM)
11q
11r
11s
11t
4-Biphenyl-CH2CH2
4-Biphenyl-CH2
PhCH2CH2CH2CH2
7.7
1.03
0.9
210
20
20
6
26.9
4.9
11.7
1.23
207
9.6
12.8
3.5
27
19
22
30
60
84
82
81
Figure 2. Dose-responsive lymphopenia for lead compound 11c relative to the
vehicle in mice 6 h after oral administration.
PhCH2CH2CH2CH2CH2 0.2
a
%L = Lymphopenia (percent decrease in circulating lymphocytes compared to
time-matched vehicle control after 6 h upon 10 mg/kg oral (PO) administration of
the corresponding alcohol.
The lead molecule 11c (PPI-4667) was further investigated
for potency in vivo when orally administered. The agonist
showed significant lymphopenia at all doses between 0.3 mg/
kg and 10 mg/kg at 6 h post-dose in mice (Fig. 2). Overall, the
lead molecule 11c demonstrated excellent dose responsiveness
when administered orally at doses between 0.3 and 10 mg/kg
with maximal activity observed at doses of 3 mg/kg and above.
Following oral dosing of the lead molecule 11c (PPI-4667) in
mice at 1 mg/kg, plasma concentrations of phosphorylated ac-
tive drug (0.4–1.0 ng/mL) were detected for 48 h after dosing
that correlated with a duration of lymphopenia of greater than
48 h.
In summary, we have generated a detailed SAR in both the phe-
nylamide and phenylimidazole scaffolds. We have obtained potent
and selective molecules in both scaffolds. The lead molecule 11c
(PPI-4667) was chosen based on its potency and selectivity for fur-
ther in vivo investigation. PPI-4667 was found to be potent and
selective with an excellent in vivo dose response and good phar-
macodynamic properties when orally administered. Further opti-
mization of this scaffold to increase in vivo conversion of
prodrug to active phosphate is warranted.
F
O
O
i
ii
R
R
Br
O
O
O
13
14
15
O
O
Boc
N
NH
R
R
iii, iv
v
NH2
NH
N
NH
Me
Me
OH
OH
17
16
Scheme 5. Reagents and conditions: (i) R-OH, KOtBu, THF, 80 °C; (ii) CuBr2, ethyl
acetate/chloroform, reflux; (iii) (R)-2-tert-butoxycarbonylamino-3-hydroxy-2-
methyl-propionic acid, Cs2CO3, DMF; (iv) AcONH4, toluene, 120 °C; (v) TFA, CH2Cl2.
ole analog of lead molecule 11c (11q) resulted in a major reduction
in potency while its C1 analog (11r) possessed excellent potency at
S1P1 with reduced selectivity with respect to 11c. The less rigid
compounds 11s and 11t had good S1P1 activity at the expense of
selectivity. The data in Table 6 confirmed the previous observation
based on receptor binding data, that compound 11c (PPI-4667) had
the best potency for S1P1 and widest selectivity profile in both the
phenylamide and phenylimidazole series.
References and notes
1. Young, N.; Van Brocklyn, J. R. Sci. World J. 2006, 6, 946.
2. Brinkmann, V.; Davis, D. M.; Heise, E. C.; Albert, R.; Cottens, S.; Hof, R.; Bruns, C.;
Prieschl, E.; Baumruker, T.; Hiestand, P.; Foster, A. C.; Zollinger, M.; Lynch, R. K.
J. Biol. Chem. 2002, 277, 21453.
3. Chueh, S.-C. J.; Kahan, B. Curr. Opin. Organ Transplan. 2003, 8, 288.
4. Evindar, G.; Bernier, S. G.; Kavarana, M. J.; Doyle, B.; Lorusso, J.; Kelley, M.;
Halley, K.; Hutchings, A.; Wright, A. D.; Saha, A. K.; Hannig, G.; Morgan, B. A.;
Westlin, W. F. Bioorg. Med. Chem. Lett. 2009, 19, 369.
Table 6
[
35S]GTP
cS functional activity on human S1P1 and S1P3 receptor subtypes
5. Commercially unavailable alcohols were synthesized as follows: (a)
1)
OH
n
H2N
Y
R
X
Q
Me
O
OH
Pd(PPh3)4, CuI
O
P
R
R
Et3N, MeCN
HO
X
Aryl
Aryl
Agonist
Y
R
Q
X
hS1P1 EC50 hS1P3 EC50 S1P3/
(nM)
2)H2, Pd/C, MeOH
n
(nM)
S1P1
OH
(b) 2-(biphenyl-4-yl)ethanol was synthesized from 2-(biphenyl-4-yl)acetic acid
via BH3 reduction at 0 °C
S1P
11a
11n
11c
11o
11p
11i
—
—
—
—
O
5.6
2.4
—
>12
0.8
231
21.8
1.1
>68
1.3
10.8
24.9
80.7
16
Amide
Amide
Amide
Amide
Amide
Amide
Amide
Amide
Imidazole 4-Ph Ph
Imidazole 4-Ph Ph
Imidazole
Imidazole
4-Ph Ph
4-Ph Ph
4-Ph Ph
4-Ph Ph
4-Ph Ph
H
H
H
247
56.1
0.52
2.9
37
44.1
1.1
2.67
2.2
37.2
7.3
>3000
47.3
120
R
CH2O
C2H4O
C3H6O
C4H8O
C4H8O
B(OH)2
OH
OH
R
63.3
42.2
>3000
1.38
28.8
54.8
>3000
117
Br
Pd(OAc)2, PPh3
Ph
Ph
CsCO3, DMF/H2O
11j
C5H10O
11m
11r
11q
11s
11t
c-Hexyl C4H8O
.
CH2O
C2H4O
C4H8O
6. Arvela, R. K.; Leadbeater, N. E. Org. Lett. 2005, 7, 2101.
7. Clemens, J. J.; Davis, M. D.; Lynch, R. K.; Macdonald, T. L. Bioorg. Med. Chem. Lett.
2003, 13, 3401.
H
H
Ph
Ph
8. Davis, D. D.; Clemens, J. J.; Macdonald, T. L.; Lynch, R. K. J. Biol. Chem. 2005, 280,
C5H10
O
10.2
285
27.9
9833.