Discovery of 3-arylpropionic acids as potent agonists of sphingosine-1-phosphate receptor-1 (S1P1) with high selectivity against all other known S1P receptor subtypes

Article abstract of DOI:10.1016/j.bmcl.2006.04.084

A series of 3-arylpropionic acids were synthesized as S1P₁ receptor agonists. Structure-activity relationship studies on the pendant phenyl ring revealed several structural features offering selectivity of S1P₁ binding against S1P

Full text of DOI:10.1016/j.bmcl.2006.04.084

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3679–3683
Discovery of 3-arylpropionic acids as potent agonists of
sphingosine-1-phosphate receptor-1 (S1P1) with high selectivity
against all other known S1P receptor subtypes
Lin Yan,a,* Pei Huo,a George Doherty,a,ꢀ Lesile Toth,a Jeffrey J. Hale,a Sander G. Mills,a
Richard Hajdu,b Carol A. Keohane,b Mark J. Rosenbach,b James A. Milligan,b
Gan-Ju Shei,b Gary Chrebet,b James Bergstrom,b Deborah Card,b
Elizabeth Quackenbush,c Alexandra Wickhamc and Suzanne M. Mandalab
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
bDepartment of Immunology and Rheumatology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
cDepartment of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 8 March 2006; accepted 21 April 2006
Available online 11 May 2006
Abstract—A series of 3-arylpropionic acids were synthesized as S1P1 receptor agonists. Structure–activity relationship studies on the
pendant phenyl ring revealed several structural features offering selectivity of S1P1 binding against S1P2–5. These highly selective
S1P1 agonists induced peripheral blood lymphocyte lowering in mice and one of them was found to be efficacious in a rat skin trans-
plantation model, supporting that S1P1 agonism is primarily responsible for the immunosuppressive efficacy observed in preclinical
animal models.
Ó 2006 Elsevier Ltd. All rights reserved.
Modulation of biological actions of sphingosine-1-phos-
R
phate receptors (S1Ps)—members of the G protein-
coupled receptor superfamily—has emerged as a new
paradigm for the discovery of therapeutic agents.1
FTY720 (1, Fig. 1) is a synthetic analog of myriocin,
an antifungal antibiotic isolated from entomopathogen-
ic fungus Isaria sinclairii.2 As a novel immunosuppres-
sant, FTY720 has progressed to phase III clinical trials
in the prevention of allograft rejection after renal trans-
plantation and phase II for the treatment of multiple
sclerosis.3 The mechanism of its action has been pro-
posed to be that 1 is phosphorylated in vivo to mono-
phosphate 24 which is an agonist of S1P1,3,4,5 receptors
but not S1P2,5 and that S1P1 agonism redirects the
trafficking of peripheral na¨ıve and activated CD4 and
O
NH2
OH
1, R = -H, FTY720
2, R = -PO3H2, FTY720 phosphate
O
N
S
F3C
CO2H
3
4
N
N
CO2H
O
N
N
Keywords: Sphingosine-1-phosphate (S1P) receptors; Agonists; Lym
phocyte lowering; Immunosuppression; Transplantation; 3-Arylprop-
ionic acids.
N
O
5
*
Corresponding author. Tel.: +1 732 594 5419; fax: +1 732 594
2210; e-mail: lin_yan@merck.com
Figure 1. Structures of FTY720 (1), its metabolite FTY720-phosphate
(2), two azetidine-3-carboxylic acids (3 and 4), and lead S1P1 receptor
agonist 5.
ꢀ
Present address: Array BioPharma, 2620 Trade Center Avenue,
Longmont, CO 80503, USA.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.04.084

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L. Yan et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3679–3683
CD8 T cells and B cells from systemic circulation into
secondary lymphoid organs, resulting in the observed
immunosuppressive efficacy in preclinical animal mod-
els.6 The primary adverse effect observed in clinical trials
of FTY720 is transient and asymptomatic bradycardia;
S1P3 agonism has been shown to be responsible for
the acute cardiovascular toxicity observed in rodents.7
further elucidated,12–14 investigation that establishes
the connection of S1P1 and alterations in lymphocyte
trafficking makes it desirable to have an S1P1-specific
agonist as an immunosuppressant. Here we describe
the discovery of a series of 3-arylpropionic acids as po-
tent S1P1 agonists derived from lead compound 5.15
Structure–activity relationship studies of the left-hand
side pendant phenyl ring identify several structural
motifs offering S1P1 agonists selective against all other
known S1P subtypes.
We have recently disclosed several series of amino acids
as potent and orally bioavailable S1P1 agonists selective
against S1P3 (exemplified by 3 and 4, Fig. 1).8–11 Com-
pound 3 is a potent S1P1 agonist (IC50 = 1.2 nM) with
good to moderate selectivity over other S1P subtypes
(440-fold over S1P3, 1350-fold against S1P4, and 20-fold
over S1P5). In comparison, compound 4 is a more
potent S1P1 agonist (IC50 = 0.6 nM) with excellent selec-
tivity against S1P3 (20,000-fold), but its selectivity over
other subtypes is low (120-fold over S1P4 as a weak
antagonist and non-selective against S1P5). While phys-
iological actions of other S1P subtypes remain to be
Based on the structural similarity between azetidine-3-
carboxylic acid 4 and lead compound 5, we decided to
introduce a carboxylic acid group to the right-hand side
phenyl ring of 5 at the position para to the oxadiazole
ring, where it may interact potentially with negatively
charged residues of S1P1 receptor (e.g., Arg120 and
Arg292).16 The distance—defined by the number (n) of
methylene groups—between the carboxylic acid group
and the phenyl ring was varied incrementally to optimize
a
O
NH2
N
CO2H
a, b
c, d
X
HO
N
N
+
CO2R
n
CO2R
n
CO2H
n
7
9
8
6a n = 0, X = Br, R = CH
6b n = 1, X = I, R = C2H5
b
NH2
O N
N
NC
g, h
HO
e, f, b
N
CO2R
+
CO2H
Br
R
CO2R
10
11a R = CH3
11b R = C(CH3)3
12
X
13
+
CO2H
O
N
c, d
N
CO2H
14
8
CO2H
c
NH2
O N
N
O N
N
HO
c
i, d
N
+
CO2H
Br
Br
n
17a n =3
17b n =5
15
16
8
d
O N
N
O N
N
X
X
R
j or k, h
CO2C(CH3)3
CO2H
Cl
N
N
18
19
X = H or Cl
Scheme 1. (a) Zn(CN)2, Pd2(dba)3, dppf, H2O, DMF, 120 °C; (b) NH2OHÆHCl, NaHCO3, CH3OH, 60 °C (10–90%); (c) EDC, ClCH2CH2Cl, rt
(4 h)—100 °C (14 h) (14–60%); (d) NaOH, CH3OH, rt (63–100%); (e) methyl acrylate or tert-butyl acrylate, Pd[P(tBu)3]2, Cy2NCH3, 1,4-dioxane,
70 °C; (f) 10% Pd/C, H2 (15 Psi), CH3OH, rt, (49% over two steps); (g) derivatized benzoic acids, EDC, ClCH2CH2Cl, rt (4 h)—100 °C (14 h); (h) 20%
TFA, CH2Cl2, rt (81%); (i) BrZn(CH2)nCO2Et, n = 3 and 5, Pd[P(tBu)3]2, 1,4-dioxane, 75 °C; (j) ROH, NaH, DMF, 120 °C; (k) RZnBr, Pd[P(tBu)3]2,
NMP, THF, 80 °C.

L. Yan et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3679–3683
3681
S1P1 binding potency. These analogs can be readily pre-
pared from commercial materials using known synthetic
methods. Synthesis of analogs having n = 0 and 1 fea-
tured palladium catalyzed cyanation (Scheme 1a). Syn-
thesis of analogs having n = 2 utilized Heck coupling
reaction (Scheme 1b). The low yielding (ꢀ10%) for the
formation of amidoxine 12 from methyl 3-phenylpropi-
onate was circumvented by using corresponding tert-bu-
tyl ester instead. Synthesis of analogs having n = 3 and 5
exploited Neigishi coupling (Scheme 1c).17 Finally, prep-
aration of pyridine analogs was achieved using either
properly derivatized pyridine carboxylic acids or chemi-
cal modification of intermediate 19 (Scheme 1d).
against S1P3 was significantly decreased and selectivity
against S1P5 was enhanced just about twofold. Com-
pound 14 was also found to lower murine PBL modestly
versus vehicle after a 1 mpk po dose. In contrast, com-
pounds having distance other than n = 2 showed greater
than fivefold S1P1 binding potency loss. Based on these
data, 3-arylpropionic acids were selected for further
investigation.
3-Arylpropionic acids having a pendant 3,4-disubstitut-
ed phenyl group demonstrated significant potency
enhancement (Table 2). Analog 13a is a 90 pM S1P1
Table 2. S1P functional binding affinities (EC50, nM) for compounds
having 3,4-disubstituted pendant phenyl ringa
S1P binding affinities (IC50) of the new compounds were
determined in competitive binding assays of [33P]-la-
beled S1P ligand on Chinese hamster ovary (CHO) cell
membranes stably expressing S1P receptors.5a Their
respective functional binding affinities (EC50) were
determined by measuring the ligand-induced uptake of
[35S]GTPcS by CHO cell membranes stably expressing
S1P receptors.5a All tested compounds were found to
be full agonists of S1P1,3,5 and inactive (IC50 > 10 lM)
against both S1P2 and S1P4. This class of carboxylic
acids appeared significantly more potent when evaluated
for functional activity as compared to receptor binding.
While reasons for such shift are not fully understood at
present, they are not unprecedented and with these com-
pounds we found EC50 values a better guide for inter-
preting in vivo activity. Compound-induced peripheral
blood lymphocyte (PBL) lowering in mice was measured
by the reduction percentage of the absolute PBL counts
determined at a three-hour time point after the oral
administration of the test compound in comparison to
those from vehicle controls.5a The murine PBL lowering
has been previously shown to correlate with immuno-
suppressive efficacy in rodents.18
O
N
R
N
CO2H
O
X
Compound
R
X
S1P1
0.09
S1P3
S1P5
40
13a
CF3
CF3
CF3
F
110
13b
13c
13d
13e
13f
13g
13h
13i
0.4
3.2
460
>10,000
4070
1500
460
260
2600
530
140
210
43
H3C
1.9
Cl
0.2
CH3
Br
0.2
Among all carboxylic acids with varying distance be-
tween the phenyl ring and the carboxylic acid group,
3-phenylpropionic acid 14 was the most potent S1P1
agonist (Table 1). Its S1P1 binding affinity was improved
about sixfold in comparison to 5; whereas, its selectivity
<0.08
1.1
230
OCH3
CN
CN
CN
CN
CN
620
270
Table 1. S1P functional binding affinities (EC50, nM) for compounds
with varying distance between the carboxylic acid and the right-hand
side phenyl groupa,b
<0.08
0.07
0.03
0.1
1100
470
6.5
O
N
CO2H
N
13j
15
n
Compound
n
S1P1
S1P3
S1P5
266
13k
13l
500
3.1
F3C
5
—
0
2.4
467
830
0.4
>10,000
>10,000
>10,000
160
9a
9b
14
17a
17b
>10,000
4000
591
F3C
F3C
1
340
0.7
2
3
14
12
1100
1220
840
1080
5
13m
0.11
1600
44
F3C
a Ligand-induced uptake of [35S]GTPcS on CHO cell membranes
expressing S1P receptors. Data are reported as means for n = 3
measurements. SD were generally within 20% of the average.
b The EC50 values of S1P2 and S1P4 are generally greater than 10 lM.
a Ligand-induced uptake of [35S]GTPcS on CHO cell membranes
expressing S1P receptors. Data are reported as means for n = 3
measurements. SD were generally within 20% of the average.

3682
L. Yan et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3679–3683
agonist, and its selectivity against S1P3 and S1P5 was
about 1200- and 450-fold, respectively. It was also able
to lower murine PBL maximally versus vehicle after a
0.1 mpk po dose. Changing isopropyl group into ethyl
and methyl groups led to the incremental loss of S1P1
binding affinity. Replacement of 3-trifluoromethyl
group of 13a yielded a series of potent S1P1 agonists.
Among them, bromide 13g and nitrile 13i were found
to be full agonists even at the lowest testing concentra-
tion (80 pM) in S1P1 functional binding assay. Com-
pound 13i showed greater than 14,000-fold of
selectivity against S1P3 and 80-fold over S1P5 and low-
ered PBL maximally versus vehicle after a 0.1 mpk po
dose. Chloride 13e is a potent S1P1 agonist with good
selectivity against both S1P3 (7500-fold) and S1P5
(700-fold). One methyl group extension of isopropyl
group in 13i led to 13j having almost threefold decrease
in selectivity against S1P3. Fluorination on the isopropyl
group of 13i resulted in equipotent S1P1 agonists but
loss of selectivity against S1P3. The latter, but not the
former, was observed previously with 2-aryl(pyrroli-
din-4-yl)acetic acids.11 Analog 13m is a potent S1P1 ago-
nist and has good selectivity against S1P3 (16,000-fold)
and S1P5 (400-fold). Both 13e and 13m were able to low-
er murine PBL modestly and maximally versus vehicle
after a 0.3 mpk po dose, respectively (Table 3).
n-butyl group with isobutyl resulted in about fivefold
potency enhancement. Fluorination of isobutyl group
led to further enhancement (fourfold); however, selectiv-
ity of S1P1 against S1P3 and S1P5 was again attenuated;
an instance was observed previously with 2-aryl(pyrroli-
din-4-yl)acetic acids.11 Translocation of the nitrogen on
the pyridine ring of 19b away from the oxadiazole ring
gave 19d, which was found to be 25-fold less potent.
Conversion of isobutyl group of 19d to isopropyloxy
furnished 19e with significant potency loss. Remarkably,
introduction of chlorine ortho to isopropyloxy of 19e
exhibited almost 300-fold potency gain, with 1400-fold
of selectivity against both S1P3 and S1P5 receptors.
Again, fluorination of isobutyl group of 19f led to fur-
ther sevenfold potency increase, but its selectivity
against both S1P3 and S1P5 was substantially decreased.
Compounds 19f and 19g showed modest ability to lower
murine PBL modestly versus vehicle after a 3 mpk po
dose and modestly after a 0.3 mpk po dose, respectively.
Rat pharmacokinetics for selected 3-arylpropionic acids
generally showed low clearance (except for pyridine
analog 19f), low volume distribution, and good oral
bioavailability (Table 4). But regardless of structural
variations on the pendant phenyl ring, 3-arylpropionic
acids all exhibited relatively short halflives in rat.
Another lead structure we have pursued in the hope of
identifying S1P1 specific agonists was pyridine analog
19a—a modest potent S1P1 agonist with excellent selec-
tivity against both S1P3 and S1P5. Replacement of
To demonstrate that an S1P1 agonist selective against
all other S1P subtypes could maintain the immunosup-
pressive efficacy of 1, compound 13m, which has the
shortest half life in rat and good selectivity against
S1P3,5, was selected to test in a skin allograft model,
using the MHC–disparate combination of DA (donor)
and Lewis (recipient) rats.19 Compound 13m (1.5 mpk/
day or 4.5 mpk/day, n = 6 rats, delivered via Alzet
mini-osmotic pumps placed in the peritoneal cavity)
and 1 (1 mpk/day, po, n = 6 rats) were administered
one day prior to graft transplantation, until graft death.
The median graft survival times were 11 days (vehicle,
n = 8 rats), 13 days (13m at 1.5 mpk/day), 14 days
(13m at 4.5 mpk/day), and 12 days (1). Graft survival
was statistically significantly enhanced by treatment
with either 1 or 13m (at either dose), but there was no
statistically significant difference between treatment with
either 1 or 13m. Treatment of 13m at higher dose, how-
ever, prolonged graft survival significantly better than
with lower one. The degree of PBL lowering achieved
at day 7 in rat, post-transplantation, was found to be
maximal for 1 and 13m at both doses, respectively.
Table 3. S1P functional binding affinities (EC50
compounds having substituted pyridyl ringa
,
nM) for test
O
N
R
N
CO2H
Compound
R
S1P1
16.0
S1P3
S1P5
19a
>10,000
1200
>10,000
N
nBu
19b
19c
19d
19e
19f
19g
3.4
0.9
>1000
820
N
470
N
F
F
88
>1000
>10,000
950
>1000
>10,000
950
N
N
N
In conclusion, a series of 3-arylpropionic acids—struc-
turally complementary to the other series of S1P1 ago-
nists discovered in these laboratories—have been
identified as potent and selective S1P1 receptor agonists.
Structure–activity relationship studies on the pendant
phenyl ring allowed for the identification of several
S1P1 potent agonists with high selectivity against other
S1P subtypes. These highly selective S1P1 agonists can
effectively lower peripheral blood lymphocytes in mice.
Compound 13m was tested in a rat skin transplantation
experiment and found to be immunosuppressive compa-
rable to 1. 3-Arylpropionic acids exhibit overall good
pharmacokinetic properties except that they have
208
0.7
O
Cl
O
Cl
0.1
160
24
F3C
O
N
a Ligand-induced uptake of [35S]GTPcS on CHO cell membranes
expressing S1P receptors. Data are reported as means for n = 3
measurements. SD were generally within 20% of the average.

L. Yan et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3679–3683
Table 4. Rat pharmacokinetic parameters of selected 3-arylpropionic acidsa
3683
Compound
Rat PK
13a
13e
13i
Clp = 8.7 mL/min/kg, Vdss = 1.1 L/kg, t1/2 = 1.1 h, %F = 88.0
Clp = 5.7 mL/min/kg, Vdss = 0.4 L/kg, t1/2 = 0.8 h, %F = 80.0
Clp = 2.3 mL/min/kg, Vdss = 0.2 L/kg, t1/2 = 0.7 h, %F = 53.0
Clp = 1.2 mL/min/kg, Vdss = 0.1 L/kg, t1/2 = 0.6 h, %F = 59.0
Clp = 13.5 mL/min/kg, Vdss = 0.9 L/kg, t1/2 = 1.0 h, %F = 78.3
13m
19f
a Plasma compound concentrations used to calculate pharmacokinetic parameters were obtained after iv administration (1.0 mpk) and po admin-
istration (2.0 mpk) of test compounds to male Sprague–Dawley rats (n = 2), respectively.
White, V.; Xie, J.; Proia, R. L.; Mandala, S. J. Pharmacol.
Exp. Ther. 2004, 309, 758; (b) Sanna, M. G.; Liao, J.; Jo,
E.; Alfonso, C.; Ahn, M.-Y.; Peterson, M. S.; Webb, B.;
Lefebvre, S.; Chun, J.; Gray, N.; Rosen, H. J. Biol. Chem.
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relatively short half life in rat. Together, these results
suggest that 3-arylpropionic acids are suitable for fur-
ther investigation with the aim of identifying highly
selective S1P1 agonists with good overall physical prop-
erties and biological activities.
8. Hale, J. J.; Lynch, C. L.; Neway, W.; Mills, S. G.; Hajdu,
R.; Keohane, C. A.; Rosenbach, M. J.; Milligan, J. A.;
Shei, G.-J.; Parent, S. A.; Chrebet, G.; Bergstrom, J.;
Card, D.; Ferrer, M.; Hodder, P.; Strulovici, B.; Rosen,
H.; Mandala, S. J. Med. Chem. 2004, 47, 6662.
9. Li, Z.; Chen, W.; Hale, J. J.; Lynch, C. L.; Mills, S. G.;
Hajdu, R.; Keohane, C. A.; Rosenbach, M. J.; Milligan, J.
A.; Shei, G.-J.; Parent, S. A.; Chrebet, G.; Parent, S. A.;
Bergstrom, J.; Card, D.; Forrest, M.; Quackenbush, E. J.;
Wickman, L. A.; Vargas, H.; Evans, R. M.; Rosen, H.;
Mandala, S. J. Med. Chem. 2005, 48, 6169.
Acknowledgments
We thank Ms. Susan Li and Dr. Larry Colwell for coor-
dinating the rat pharmacokinetics studies.
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