Identification of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives and their orally active prodrug esters as dual-acting alpha4-beta1 and alpha4-beta7 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2012.12.026

N-Acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives of type 4 were designed to replace the 2,6-dichlorobenzoylamine portion of compound 1 in order to identify novel compounds with improved potency against α4-integrins. Several derivatives were identified as very potent dual-acting α4-integrin, α4β1 and α4β7 antagonists. Investigation of a limited number of prodrug esters led to the discovery of the ethyl ester prodrug 42, which demonstrated good intestinal fluid stability and good permeability. Despite low solubility, 42 gave acceptable blood levels of 30 when dosed orally in non-human primates. Additionally, 42 had an overall excellent profile and was selected for clinical trials. Investigation of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives led to the discovery of several very potent dual-acting α4-integrin antagonists. Ethyl ester prodrug 42 advanced to human clinical trials based on the excellent intestinal fluid stability, good permeability and superior efficacy in non-human primates.

Full text of DOI:10.1016/j.bmcl.2012.12.026

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1026–1031
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine
derivatives and their orally active prodrug esters as dual-acting
alpha4–beta1 and alpha4–beta7 receptor antagonists
a
a
b
b
c
Achyutharao Sidduri a, , Jefferson W. Tilley , Jianping Lou , Nadine Tare , Gary Cavallo , Karl Frank ,
⇑
Anjula Pamidimukkala c, Duk Soon Choi d, Louise Gerber d, Aruna Railkar d, Louis Renzetti b
a Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA
b Discovery Inflammation and Respiratory Diseases, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA
c Drug Metabolism and Pharmacokinetics, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA
d PARD, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives of type 4 were designed to replace the 2,6-
dichlorobenzoylamine portion of compound 1 in order to identify novel compounds with improved
Received 19 October 2012
Revised 28 November 2012
Accepted 10 December 2012
Available online 20 December 2012
potency against
a4-integrins. Several derivatives were identified as very potent dual-acting a4-integrin,
a
4b1 and 4b7 antagonists. Investigation of a limited number of prodrug esters led to the discovery of
a
the ethyl ester prodrug 42, which demonstrated good intestinal fluid stability and good permeability.
Despite low solubility, 42 gave acceptable blood levels of 30 when dosed orally in non-human primates.
Additionally, 42 had an overall excellent profile and was selected for clinical trials. Investigation of N-acyl
4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives led to the discovery of several very potent dual-
Keyword:
Alpha4 beta1 and alpha4 beta7 integrin
antagonists
acting
a4-integrin antagonists. Ethyl ester prodrug 42 advanced to human clinical trials based on the
excellent intestinal fluid stability, good permeability and superior efficacy in non-human primates.
Ó 2012 Elsevier Ltd. All rights reserved.
Cl
O
OCH3
H
N
Alpha4 integrins are expressed on a variety of leukocytes,
including B-cells, T-cells, basophils and eosinophils, and are in-
volved in the recruitment, activation and survival of these cell
types.1 Data supporting a role for alpha4 integrins in a number of
inflammatory diseases, including asthma, rheumatoid arthritis,
multiple sclerosis (MS), inflammatory bowel diseases, and athero-
Cl
OCH3
Cl
OH
OH
Cl
HN
HN
Cl
O
O
O
O
sclerosis, has emerged and is summarized in recent reviews.2
A
CH3
humanized mouse anti-alpha4 antibody, Natalizumab, has been
approved for the treatment of multiple sclerosis3 and Crohn’s dis-
ease.4 Very recently a small molecule alpha4 integrin antagonist
was shown to be effective for the treatment of MS,5 fully validating
alpha4 integrins as targets for human disease.
2
1
Alpha4-beta1 IC50 = 10 nM
Alpha4-beta7 IC50 = 43 nM
We previously reported that the potent, dual-acting antagonist
CH3
N
of a4b1 and a4b7, 1, (Fig. 1) is effective for the treatment of asthma
R1
N
O
N
in humans6 and sought additional compounds that might have
lower clearance and novel structures with superior potency for
O
O
N
both alpha4 integrins, a4b1 and a4b7.
OCH3
Cl
R2
Inspired by reports of the alpha4 integrin antagonist activity of
members of the biphenylalanine class such as 2,7 as well as the
interesting, selective integrin antagonist activity of members of
the pyridizinone family represented by 3,8 we report here the dis-
covery of a new series of potent alpha4 integrin antagonists, N-acyl
R3
OH
HN
Cl
OH
O
HN
R4
O
O
O
3
4
⇑
Corresponding author. Tel.: +1 973 235 7143; fax: +1 973 235 7122.
E-mail address: sidduria@yahoo.com (A. Sidduri).
Figure 1. Structures of reported alpha4 integrin antagonists.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.12.026

A. Sidduri et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1026–1031
1027
Table 1
Table 2
SAR summary of R4 modifications
SAR summary of R3 and R4 modifications
Me
N
Me
N
O
O
O
O
Me
N
N
Me
Me
R3
OH
OH
HN
R4
HN
R4
O
O
O
O
Compd
R4
a4b1 Ramos cells/VCAM IC50 nM
Compd R3
R4
a
4b1 Ramos
a4b7 RPMI cells/
MadCAM IC50 nM
(Rel potency)
(Rel potency)a
cells/VCAM IC50
nM (Rel potency)
Me
Cl
Cl
21
81 (1.0)
Cl
Br
25
26
27
CH3
8 (6.3)
35 (16)
Me
Cl
Cl
Cl
Cl
22
25 (2.0)
CF3
196 (0.46)
35 (2.1)
219 (1.3)
58 (6.1)
O
O
H3C
23
24
255 (0.35)
64 (0.8)
Me
Me
Br
CH3
H3C
a
Rel potency refers to activity relative to the reference standard 1 run as a
positive control in each binding experiment.
28
29
30
CF3
123 (0.1)
287 (0.49)
18 (3.2)
167 (2.4)
324 (1.0)
81 (3.3)
O
4-(5-pyrimidine-2,4-dionyl)-phenylalanine derivatives 4 (Fig. 1)
and their orally active prodrug esters.
H3C
CH3
CH3
The compounds reported in Tables 1–4 were prepared by a
crucial palladium-catalyzed coupling reaction of the 4-iodophenyl-
alanine derivatives 6 or 13 with an in situ generated organozinc
intermediate (Schemes 1 and 2) that was derived from the 1,
3-disubstituted-5-iodo-pyrimidine-2,4-dione, the 1,3,6-trisubsti-
tuted-5-iodo-pyrimidine-2,4-dione (5) or the 1,3-disubstituted-6-
trifluoromethyl-5-iodo-pyrimidine-2,4-dione (16) (Scheme 3).
The desired intermediate 5-iodo-pyrimidine-2,4-dione deriva-
tives were prepared by alkylation or iodination reactions, as per lit-
erature procedures.9 The iodide derivatives were then reacted with
an activated zinc dust in dimethylacetamide at 70 °C to give the
corresponding organozinc intermediates.10 The coupling reaction
of this organozinc intermediate with 6 proceeded smoothly in
the presence of Pd(dba)2 and trifurylphosphine (TFP) or tri-ortho-
tolylphosphine in THF at 55 °C to afford the desired product in
good yield. The remaining steps, BOC removal, benzoylation, and
hydrolysis proceeded in a straightforward manner to obtain the
target compounds (Scheme 1).
F
F
Cl
Cl
31
32
CH3
CH3
87 (0.53)
151 (2.3)
558 (1.0)
CH3
CH3
215 (0.13)
CH3
CH3
H3C
33
CH3
1450 (0.04)
1970 (0.15)
CH3
CH3
The synthesis of the 3-methyl-4-iodophenylalanine (13) and the
corresponding target compounds 14 are shown in Scheme 2. Thus,
3-methyl-4-nitrobenzyl alcohol 9 was converted to the desired io-
dide 13 in six steps. The crucial step in this process was the chiral
hydrogenation of olefin 11 to the (S)-phenylalanine 12 using a chi-
ral rhodium catalyst, (+)-1,2-bis((2S,5S)-2,5-dimethylphospholano)
benzene(cyclooctadiene)rhodium(I) trifluoromethanesulfonate
([[Rh(COD)(S,S)-(me)DuPHOS]+TfOꢀ]) in methanol. Deprotection
followed by diazotization under Sandmeyer reaction conditions
gave the iodide 13. Coupling of 13 with an in situ generated organo-
zinc reagent (prepared from pyrimidinedione 5) gave the expected
3,4-disubstituted phenylalanine derivative which was converted to
the target compound 14 in three straight forward steps.
crotonate and methyl isocyanate using a method previously described
as shown in Scheme 3.11
The 2-chloro-6-alkyl substituted benzoic acid derivatives (19)
were prepared following Scheme 4. The crucial step in this scheme
was the displacement of an ortho-fluorine from N-(2-chloro-6-
fluorobenzylidine)butylamine 18 with alkylmagnesium bromides.
Deprotection of the imines, followed by oxidation gave the corre-
sponding benzoic acids, 19.
In general, alkyl ester prodrugs such as 20 were prepared by
treatment of the carboxylic acids with the appropriate alkyl iodides
or alkyl bromides in the presence of sodium bicarbonate in DMF as
shown in Scheme 5.
The 1,3-dimethyl-6-trifluoromethyl-5-iodopyrimidine-2,4-dione
(16) was prepared in three steps from ethyl 3-amino-4,4,4-trifluoro-

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A. Sidduri et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1026–1031
R1
N
Table 3
SAR summary of R4 modifications with R1 and R2 as ethyl group
O
O
R1
N
N
R2
CH3
O
O
I
a, b
R3
O
N
O
N
R2
O
I
R3
H3C
N
HN
O
CH3
O
O
5
O
OH
HN
HN
R4
4b1 Ramos cells/
7
O
O
O
O
O
6
Compd
R4
a
a4b7 RPMI cells/
VCAM IC50 nM
(Rel potency)
MadCAM IC50 nM
(Rel potency)
R1
N
O
O
Cl
N
R2
34
63 (0.80)
124 (4.8)
c, d, e
R3
Cl
Cl
OH
Me
HN
R4
O
35
36
296 (0.37)
382 (0.29)
164 (1.7)
O
8
O
H3C
Scheme 1. Reagents and conditions: (a) Zn dust (activated using 10 mol % of 1,2-
dibromoethane and 10 mol % of TMSCl in THF), DMAC, 70 °C, 3–15 h; (b) Pd(dba)2,
TFP or tri-ortho-tolylphosphine, THF, 50 °C, 15 h, 42–73%; (c) 4.0 N HCl in dioxane,
dioxane, rt, 5 h, 91–99%; (d) R4COOH, HBTU, DIPEA, DMF, rt, 15 h, 72–95% or
R4COCl, DIPEA, CH2Cl2, rt, 15 h, 80–93%; (e) 1.0 N NaOH, EtOH, rt, 5–15 h, 85–95%.
565 (0.46)
Table 4
SAR summary of R3 and R4 modifications with 3-methyl-L-phenylalanine derivatives
data in Tables 1–4 are reported both as the observed IC50 and as
fold-potency relative to 1 since the activity of the cell lines varied
over time with the number of passages.
We had previously proposed a binding model for 1 that in-
cluded as a4b1 recognition elements a p-stacking interaction with
the phenylalanine and attached electron deficient benzoyl moiety
as well as a hydrogen bonding interaction with the phenylalanine
4-carboxamido group.12 The first compounds prepared in the
pyrimidinedione series incorporate those features. As shown in Ta-
Me
O
N
O
Me
N
Me
R3
OH
HN
R4
4b1 Ramos cells/
O
ble 1 they have similar potency in our a4b1 binding assay to 1. The
O
data also support the notion that in this series, in order to achieve
high potency, the phenylalanine should bear a 2,6-disubstituted
benzoyl functionality as seen with 21 and 22.13
Compd
R3
R4
a
a4b7 RPMI cells/
VCAM IC50 nM
(Rel potency)
MadCAM IC50 nM
(Rel potency)
Drawing on the observation that 20,60-disubstitution on the dis-
tal aromatic ring is a requirement for high potency in 2, we fol-
lowed up with a series of analogues of 21 and 22 that included a
substituent in the 6-position of the pyrimidinedione ring as shown
in Table 2. We quickly made the following observations: first, addi-
tion of a 6-methyl substitution gave a 5- to 10-fold improvement in
potency for both integrins; second, replacement of 6-methyl with
6-trifluoromethyl reduced potency drastically; third, the aroyl ser-
ies again maintained a higher potency than the corresponding
cycloalkanoyl series; and finally, a substitution bulkier than methyl
or chloro at the 2- or 2,6-positions on the N-acyl aromatic ring gave
a marked reduction in potency, which was consistent with our pre-
vious observations.13
Cl
37
38
39
H
246 (0.14)
56 (0.68)
10 (1.1)
254 (1)
CH3
Cl
Cl
H
220 (1.9)
168 (3.6)
Cl
Cl
CH3
Next, we decided to investigate the role of N-alkyl groups on the
pyrimidinedione ring. It is clear from these examples (Table 3) that
the N-methyl is preferred over the corresponding N-ethyl ana-
logues, (25 vs 34 and 27 vs 35) suggesting that this hydrophobic
pocket has very limited steric tolerance.
The in vitro potency of the compounds listed in Tables 1–4 were
assessed by determining the ability of serial dilutions to inhibit the
binding of RAMOS cells (
a4b1-specific binding) and RPMI 8866
cells ( 4b7-specific binding) with recombinant human VCAM-1
a
We presumed that the 6-methyl group on the pyrimidinedione
ring is required to promote a preferred torsion angle between the
phenylalanine aromatic ring and the pyrimidinedione. In this case,
we thought that we could achieve a similar result through the
introduction of a methyl group at the 3-position of the benzene
used as a counter ligand for the RAMOS cell assay and human MAd-
CAM-1 for the RPMI 8866 cell assay. Cells were labeled with Calce-
in AM, a fluorescent dye, and then activated with a binding buffer
containing Mn2+ to achieve maximum activation prior to the assay.
Compound 1 was used as a positive control on each plate.12 The

A. Sidduri et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1026–1031
1029
Me
H
O
N
O
Me
Me
N+
O
H
N
a, b
c
O
O
O
HN
O
H
O
OH
O
O
O
9
10
11
Me
Me
H
N
I
O
d
e, f
O
O
HN
O
HN
O
O
O
O
O
O
13
12
Me
N
Me
N
O
O
O
O
Me
N
N
Me
ZnI
Me
R3
R3
g, h, i, j
OH
HN
R4
O
O
14
Scheme 2. Reagents and conditions: (a) Boc2O, H2, Pd/C, EtOAc, rt, 2 h, 76%; (b) MnO2, CH2Cl2, 4 Å MS rt, 15 h, 77%; (c) N-(benzyloxycarbonyl)-
a-phosphonoglycine methyl
ester, tetramethylguanidine, CH2Cl2, ꢀ30 °C to rt, 15 h, 58%; (d) [[Rh(COD)(S,S)-(me)DuPHOS]+TfOꢀ], H2 (60 psi), MeOH, rt, 22 h, 55%; (e) 4.0 N HCl in dioxane, dioxane, rt, 2 h,
87%; (f) sodium nitrite, H2SO4, KI, H2O, ꢀ10 °C to rt, 1 h, 64%; (g) Pd(dba)2, tri-ortho-tolylphosphine, THF, 50 °C, 15 h, 30–69%; (h) 10% Pd/C, cyclohexene, EtOH, reflux, 20 min,
72–83%; (i) R4COOH, HBTU, DIPEA, DMF, rt, 15 h, 70% or R4COCl, DIPEA, CH2Cl2, rt, 15 h, 48–81%; (j) 1.0 N NaOH, EtOH, rt, 5–15 h, 41–93%.
Me
N
H
O
H
N
HO
O
O
F
F
O
O
a, b
F
a
b, c, d
O
Cl
F
Cl
Cl
R
F
CH3NCO
+
N
Me
H2N
F
F
F
17
18
19
15
Me
N
Scheme 4. Reagents and conditions: (a) n-butylamine, heptane, rt, 3 h, 97%; (b)
RMgBr, THF, 5–20 °C, 5 h; (c) 20% HCl in H2O, 0 °C to rt, 15 h, 75–90% (in two steps);
(d) monobasic sodium phosphate, H2O2, sodium chlorite, CH3CN, H2O, 0 °C, 15 h,
80–97%.
c
O
O
I
N
Me
F
F
F
R1
N
R1
N
O
O
16
O
O
N
R2
N
Scheme 3. Reagents and conditions: (a) NaOMe, DMSO, mol. seives, 0 °C to rt, 15 h,
63%; (b) MeI, K2CO3, DME, reflux, 4 h, 83%; (c) NIS, CF3COOH, (CF3CO)2O, reflux,
15 h, 66%.
R2
R3
R3
a
O
R5
OH
HN
R4
HN
R4
ring. The data shown in Table 4 indicate that the ligand binding
interactions are more complex and a 3-methyl group on the phen-
ylalanine aromatic ring is not well tolerated in the presence or ab-
sence of substitution in the 6-position on the pyrimidinedione ring.
O
O
O
O
8
20
Among the potent
a4b1 antagonists discovered in the present
Scheme 5. Reagents and conditions: (a) R5-I or R5-Br, NaHCO3, DMF, rt, 15 h, 49–
77%.
work, we focused on the 20,60 disubstituted derivatives 25, 27
and 30 since these compounds had excellent potency against both
a
4b1 and
a
4b7 integrins and no safety flags. Based on our previous
order to achieve reasonable bioavailability, we would need to in-
voke a prodrug strategy.6
experience with phenylalanine derivatives, we realized that in

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A. Sidduri et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1026–1031
Table 5
LogD, Papp permeability and rat oral bioavailability of 3 parent compounds and their
ester prodrugs
Parent/prodrug
LogD
Papp (nm/s)
F (%) (rat)
25
40
27
41
30
42
43
ꢀ2.02
2.01
13.3
183
29
347
7.7
1.7
6
10
25
ND
9
ꢀ1.76
2.24
ꢀ2.36
1.73
1.61
269
120
30
Thus, a relatively small number of prodrugs were prepared.
Each was assessed for its logD, solubility, stability and permeabil-
ity. As expected, the ester prodrugs have an improved logD and
Papp permeability in comparison to their parent compounds (25
vs 40, 27 vs 41, and 30 vs 42, 43) (Table 5). The top 4 candidates
(Fig. 2) that emerged from these studies were profiled in rat PK
studies (Table 5) using an aqueous suspension of the compound
in a vehicle containing hydroxypropylcellulose (2% w/v) and
Tween 80 (0.1% w/v). The improved permeability of the prodrugs
compared to parent translated into improved PK profiles.
Compounds were discriminated based on their activity in the
atopic non-human primate allergic asthma model. Animals were
challenged with ascaris suum extract, to which they were allergic,
4 h after oral dosing with drug. After 48 h the bronchoalveolar la-
vage fluid was examined for the presence of inflammatory cells in
comparison with vehicle-treated controls. Of the 3 ethyl ester pro-
drugs that were profiled in this study, compound 42 was the most
effective (Fig. 3) in profoundly reducing the number of neutrophils,
eosinophils, and lymphocytes in this model. Unfortunately, the ace-
tal prodrug 43 formed inconsistent ratios of diastereomers that
were difficult to separate, and thus 43 was not further pursued.
Based on the potency, solubility, stability, oral bioavailability
and in vivo efficacy, the ethyl ester 42 was selected as a develop-
ment candidate. The pharmacokinetic properties of 42 and its par-
ent compound 30 in mouse, rat, dog and cynomolgus monkey are
shown in the Tables 6 and 7. The clearance in mice, rats and mon-
keys were good although relatively high in dogs. As a result, the
Figure 3. Allergen-induced inflammatory cell influx in the atopic non-human
primate.
Table 6
Pharmacokinetic parameters of compound 30 following iv administration
Dose
(mg/kg)
AUC0–8 h(ng h/ml)
CL
T1/2
(h)
MRT
(h)
(ml/min/kg)
Mouse
Rat
Dog
MK
10
10
5
7894
41,532
2790
21
4.8
29.7
6.88
0.26
0.61
0.21
0.25
0.19
1.46
10
22,161
Table 7
Pharmacokinetic parameters of compound 30 following po administration of 42
Dose (mg/
kg)
Tmax (h) Cmax (ng/
AUC0–24 h (ng h/
ml)
F (%)
ml)
Mouse 50
0.25
1.3
1
2988
5287
471
8547
18,097
1690
3146
22
9
6
CH3
N
CH3
N
Rat
Dog
MK
50
50
30
O
O
O
O
2
337
7
N
N
H3C
H3C
CH3
CH3
O
O
Cl HN
AUC was low in dogs. In mouse, the oral bioavailability was
ꢁ22%, however in the rats, dogs and monkeys it was low (<10%)
using different formulation approaches or at higher doses.
Compound 42 was advanced to human clinical trials and formu-
lations using reduced particle size provided the desired exposure.
In conclusion, N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine
derivatives 4 were designed to replace the 2,6-dichlorobenzoyl-
amine portion of compound 1 in order to identify a novel series
Cl HN
O
O
O
O
CH3
Cl
40
41
CH3
N
CH3
N
O
O
O
O
with improved potency in both
a4-integrins. Several derivatives
were identified as very potent dual-acting
a
4-integrin antagonists
N
N
H3C
H3C
from this discovery effort. Investigation of a limited number of
prodrug esters led to the discovery of the ethyl prodrug 42 as a
development candidate.
CH3
CH3
O
O
O
F
HN
F
F
HN
O
O
O
O
O
References and notes
F
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42
43
Figure 2. Structures of representative prodrug esters.

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