Quinolone-based IMPDH inhibitors: Introduction of basic residues on ring D and SAR of the corresponding mono, di and benzofused analogues

Article abstract of DOI:10.1016/S0960-894X(02)00945-9

The synthesis and the structure-activity relationships (SAR) of analogues derived from the introduction of basic residues on ring D of quinolone-based inhibitors of IMPDH are described. This led to the identification of compound 27 as a potent inhibitor of IMPDH with significantly improved aqueous solubility over the lead compound 1.

Full text of DOI:10.1016/S0960-894X(02)00945-9

Bioorganic & Medicinal Chemistry Letters 13 (2003) 547–551
Quinolone-Based IMPDH Inhibitors: Introduction of Basic
Residues on Ring D and SAR of the Corresponding Mono,
Di and Benzofused Analogues
T. G. Murali Dhar,* Scott H. Watterson, Ping Chen, Zhongqi Shen, Henry H. Gu,
Derek Norris, Marianne Carlsen, Kristin D. Haslow, William J. Pitts, Junqing Guo,
John Chorba, Catherine A. Fleener, Katherine A. Rouleau, Robert Townsend,
Diane Hollenbaugh and Edwin J. Iwanowicz*
Bristol-Myers Squibb PRI, Princeton, NJ 08543-4000, USA
Received 14 August 2002; accepted 1 October 2002
Abstract—The synthesis and the structure–activity relationships (SAR) of analogues derived from the introduction of basic residues
on ring D of quinolone–based inhibitors of IMPDH are described. This led to the identification of compound 27 as a potent inhibitor
of IMPDH with significantly improved aqueous solubility over the lead compound 1.
# 2002 Elsevier Science Ltd. All rights reserved.
The identification and development of inhibitors of
inosine monophosphate dehydrogenase (IMPDH)
activity, with reduced GI-related disorders common for
CellCept1, has been an active area of research.1,2 In the
accompanying communication,3 we have described our
efforts in designing quinolone-based inhibitors of
IMPDH. Although compounds with good enzyme and
cell potency were identified in this series, poor physico-
chemical properties, particularly aqueous solubility, were
an issue limiting the progression of these compounds for
in vivo studies. For example, the aqueous solubilty of
our lead compound 1 (Fig. 1) was 0.001 mg/mL.4
Figure 1. Chemical structures of MPA and quinolone 1.
chemical profile, but at a cost in binding affinity.3
Additionally, unlike mycophenolic acid analogues
where the carboxylic acid functionality is a requirement
for high potency, we have found that the introduction
of acid functionality results in a reduction of binding
affinity, regardless of whether the acid residue is posi-
tioned to mimic the MPA/IMPDH interaction5 or
directed toward solvent to enhance aqueous solubility.
Notably, in previous classes of IMPDH inhibitors,
introduction of basic residues has enhanced aqueous
solubility while maintaining or improving cell
potency.1,6 We were interested in exploring whether a
similar trend would hold for the quinolone-based series
of inhibitors, and our results are summarized in Tables
1–3.
In this communication, we describe the synthesis and
the structure–activity relationships of mono-substituted,
di-substituted and benzofused analogues derived from
the introduction of basic residues on the D-ring. This
led to the identification of potent compounds with sig-
nificantly improved aqueous solubility. In the previous
communication, we have shown that small liphophillic
residues at the 3- and 4-positions on the D-ring are
tolerated. On the other hand, small polar functionality
may provide compounds with a more favorable physio-
The synthetic pathways utilized in the preparation of
these compounds are outlined in Schemes 1–5. Com-
pounds 2–10 in Table 1 were synthesized employing the
*Corresponding authors. Tel.:+1-609-252-4158; fax:+1-609-252-
6804; e-mail: dharm@bms.com; (T. G. M. Dhar), tel.:+1-609-252-
5416; e-mail: iwanowie@bms.com (E. Iwanoowicz).
0960-894X/03/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00945-9

548
T.G.M.Dhar et al./ Bioorg.Med.Chem.Lett.13 (2003) 547–551
Table 2. SAR of 6,6-fused analogues
Table 1. SAR of bis-substituted phenyl analogues
R1
R2
IMPDH II
IC50, mM IC50, mM
CEM
Compd
X
Y
Z
IMPDH II
IC50, mM
CEM
IC50, mM
Compd
13
14
¼O
CH2
CH2
C
CH
<0.010
0.083
0.52
3.4
MPA
2
NA
NA
H
0.014
0.39
—
OH
<0.005
15
16
CH2
O
CH
CH
0.015
0.021
0.37
0.72
3
4
H
0.021
0.005
1.1
Me
H
0.65
17
18
O
O
CH
N
0.033
0.014
1.4
1.3
5
0.016
0.053
1.7
2.2
Ac
6
H
triflate derivative of 7-hydroxytetralin-1-one,9 6-bromo-
tetrahydrobenzopyran-4-one, and 6-bromo-4-N-acetyl
benzoxazine,10 respectively. Compounds 14 and 15 were
prepared from 13 as outlined in Scheme 6.
7
Me
OMe
H
0.026
1.1
8
0.140
10
9
0.025
2.7
The in vitro inhibitory potencies of compounds, fashioned
with a basic residue, against IMPDH II are outlined in
Table 1. The basic residues are attached to the terminal
phenyl moiety (D-ring). Combinations evaluating the
effects of the introduction of a second substituent
(Me- and MeO-) were also explored. Introduction of a
morpholino (2) or N-methyl piperzinyl (5) residue at the
3-position of the D-ring was preferential to the corre-
sponding analogues substituted at the 4-position (3 and
6). As reported in the accompanying communication,
substitution at the 3- and 4- positions was the preferred
bis-substitution pattern. The introduction of a methyl
residue at the 4-position of analogues fashioned with a
basic residue at the 3-position led to analogues of simi-
lar potency. This can be seen in the comparison of 2, 5,
and 9 with 4, 7, and 10, respectively. Introduction of a
methoxy residue at the 4-position in combination with
10
11
12
Me
Me
Me
0.015
0.78
0.60
0.71
<0.005
<0.005
Buchwald protocol7 on an appropriately substituted
bromoquinolone.3 A representative example is outlined
in Scheme 1. Compounds 11 and 12 were synthesized in
an analogous fashion by alkylation of the correspond-
ing quinolone phenol.
Representative examples for the synthesis of the indane-
quinolone series of IMPDH inhibitors (Table 3) are
outlined in Schemes 2–5.8 Compounds 13 and 16–18
(Table 2) were prepared in a manner analogous to the
sequence outlined in Schemes 2 and 3 starting from the
Scheme 1.
Scheme 2.

T.G.M.Dhar et al./ Bioorg.Med.Chem.Lett.13 (2003) 547–551
549
Table 3. SAR of 6,5-fused analogues
Compd
X
IMPDH II
IC50, mM
CEM
IC50, mM
Compd
X
IMPDH II
IC50, mM
CEM
IC50, mM
19
0.028
0.011
3.1
—
27
0.006
0.055
0.29
20
21
22
28
29
30
4.1
0.018
0.012
1.1
1.1
0.006
0.013
0.80
0.67
23
24
0.018
0.068
1.8
31
0.020
1.1
>10
32
33
0.030
0.015
>10
25
26
0.012
0.014
1.6
1.1
0.70
Scheme 4.
Scheme 3.

550
T.G.M.Dhar et al./ Bioorg.Med.Chem.Lett.13 (2003) 547–551
Scheme 5.
Scheme 6.
an N-methyl piperazinyl residue at the 3-position led to
an almost 10-fold loss in potency (3 vs 8). Compounds
11 and 12 were fashioned with a basic residue and a
lipophilic moiety, respectively tethered to the 3-postion
via an ether linkage. Both analogues were highly potent
inhibitors against IMPDH II and showed comparable
potency in the CEM proliferation assay.11
efforts focused on the modification of the indane system
at the 1-position. As is evident in Table 3, this structural
class led to very potent inhibitors of IMPDH II. The
fact that basic and charged residues (imidazole 24 and
trimethylammonium salt 32) are tolerated in this region
may indicate that groups anchored off the 1-position of
the indane ring are directed toward solvent accessible
regions of the protein.12 The iso-indole derivative 26 is a
potent inhibitor of IMPDH II but is only a micromolar
inhibitor of T-cell proliferation, as judged by the CEM
assay. From Tables 1–3, it is clear that the N,N-di-
methylamino indane derivative 27 is the most potent
compound with respect to the inhibition of IMPDH II
(IC50=6 nM; IMPDH I IC50=27 nM) and the T-cell
proliferation response in a CEM cell line (IC50=0.29
mM). More importantly, 27 has significantly improved
aqueous solubility (0.45 mg/mL) when compared to
compound 1 (0.001 mg/mL).4 The position of attach-
ment of the dimethylamino moiety at the 1-position of
the indane ring is clearly important since the isomeric
3-substituted dimethylamino indane 28 is 9 fold less
potent than 27 and is only a modest inhibitor of the
T-cell proliferation response.
Although potent compounds were obtained in the
monosubstituted and disubstituted series, cell potency
was less than optimal. Synthetic studies were expanded
through the formation of an additional ring fused to the
D-ring at positions 3 to 4 with the aim of maintaining
enzyme activity while improving on cell potency. Since
substitution at the 3-postition of the D-ring gave com-
pounds which were 3- to 4-fold more potent than the
corresponding 4-substituted analogues (compounds 2, 3
and 5, 6, Table 1), most of our efforts were focussed on
introducing substituents at position 1 of the benzofused
analogues. The SAR of the 6,6 and 6,5 benzofused
analogues are summarized in Tables 2 and 3.
Table 2 reports the in vitro IC50 values of analogues
based on a fused six-membered ring addition. Ketone
13, a potent inhibitor of IMPDH II and T cell pro-
liferation, showed the potential of this strategy. Modifi-
cation to enhance aqueous solubility through the
addition of polar functionality led to potent analogues.
Oxygen introduction within the E-ring gave less potent
analogues, similar to what was observed for the introduc-
tion of an oxygen atom in the bis-substituted examples
(Table 1).
The enantiomers of compound 27 were separated using
a CHIRALPAK1 AS column, and their potency
against IMPDH II enzyme and in T-cell proliferation
assays was established. As Table 4 indicates, both com-
pounds were very potent inhibitors of IMPDH II.
However, isomer A demonstrated a 2–3-fold improve-
ment in inhibiting the proliferation of T-cells as judged
by the CEM and PBL assays.12
In addition to fusing a six-membered ring to the D-ring,
we also chose to investigate analogues based on a five-
membered system, as summarizes in Table 3. Early
In summary, analogue 34 has been identified as the lead
compound in the quinolone series of IMPDH inhibi-
tors. Determination of the absolute stereochemistry of
the dimethylamino group and in vivo evaluation of in a
T-cell mediated pharmacodynamic model is in progress
and will be reported in due course.
Table 4.
References and Notes
1. Dhar, T. G. M.; Shen, Z.; Guo, J.; Liu, C.; Watterson,
S. H.; Gu, H. H.; Pitts, W. J.; Fleener, C. A.; Rouleau, K. A.;
Sherbina, N. Z.; McIntyre, K. W.; Witmer, M. R.; Tredup,
J. A.; Chen, B.-C.; Zhao, R.; Bednarz, M. S.; Cheney, D. L.;
MacMaster, J. F.; Miller, L. M.; Berry, K. K.; Harper, T. W.;
Barrish, J. C.; Hollenbaugh, D. L.; Iwanowicz, E. J. J.Med.
Chem. 2002, 45, 2127.
Compd
Enantiomer
IMPDH II
IC50, mM
CEM
IC50, mM
PBMC
IC50, mM
VX-497
MPA
34
NA
NA
A
0.010
0.014
<0.005
<0.005
0.49
0.39
0.27
0.55
0.17
0.06
0.12
0.32
35
B

T.G.M.Dhar et al./ Bioorg.Med.Chem.Lett.13 (2003) 547–551
551
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