SAR of PXR transactivation in benzimidazole-based IGF-1R kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.01.087

The SAR of PXR transactivation by 3-(benzimidazol-2-yl)-pyridine-2-one based ATP competitive inhibitors of Insulin-like Growth Factor 1 Receptor kinase (IGF-1R) is discussed. Compounds without PXR transactivation, with in vivo antitumor activity, reduced

Full text of DOI:10.1016/j.bmcl.2010.01.087

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1744–1748
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
SAR of PXR transactivation in benzimidazole-based IGF-1R kinase inhibitors
a
a
a
a
Kurt Zimmermann a, , Mark D. Wittman , Mark G. Saulnier , Upender Velaparthi , Xiaopeng Sang ,
David B. Frennesson a, Charles Struzynski a, Steven P. Seitz b, Liqi He b, Joan M. Carboni c, Aixin Li c,
Ann F. Greer c, Marco Gottardis c, Ricardo M. Attar d, Zheng Yang e, Praveen Balimane e, Lorell N. Discenza c,
Francis Y. Lee c, Michael Sinz e, Sean Kim e, Dolatrai Vyas a
*
a Oncology Chemistry, Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492, USA
b Oncology Chemistry, Bristol-Myers Squibb Co., Province Lane, Princeton, NJ 08540, USA
c Oncology Drug Discovery, Bristol-Myers Squibb Co., Province Lane, Princeton, NJ 08540, USA
d Ortho Biotech Oncology R&D/Centocor R&D Inc., 145 King of Prussia Road, Radnor, PA 19087, USA
e Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The SAR of PXR transactivation by 3-(benzimidazol-2-yl)-pyridine-2-one based ATP competitive inhibi-
tors of Insulin-like Growth Factor 1 Receptor kinase (IGF-1R) is discussed. Compounds without PXR trans-
activation, with in vivo antitumor activity, reduced protein binding and improved oral exposure are
presented.
Received 7 December 2009
Revised 4 January 2010
Accepted 6 January 2010
Available online 21 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
PXR
Pregnane X receptor
SAR
PXR transactivation
Insulin-like Growth Factor 1 Receptor
kinase
IGF-1R
CYP3A expression
Cytochrome P450
The pregnane X receptor (PXR) is a member of the nuclear
receptor family of ligand-activated transcription factors. PXR regu-
lates gene expression of several CYP450s and other enzymes in-
volved in phase I and phase II drug metabolism, as well as drug
transport.1–3 PXR transactivation can thereby lead to unwanted
drug–drug interactions and is an undesired property of compounds
considered for development as a drug. For example, the antibiotic
Rifampicin is a strong PXR transactivator and has limited use in hu-
mans because of this reason.
The ligand binding site of human PXR is large and flexible. It con-
sists of 20 hydrophobic amino acids, four amino acids with polar side
chains (Ser208, Ser247, Cys284, and Gln285) and four that are (poten-
tially) charged (Glu321, His327, His407, and Arg410).3 A salt bridge
between Glu321 and Arg410 effectively neutralizes their charge leav-
ing the binding cavity relatively hydrophobic. Due to its flexibility
the hPXR ligand binding site can accommodate (as an induced fit)
molecules that range in size from 300 to 800 Da.4,5
Only a few X-ray structures of compounds bound to the ligand
binding site of hPXR have been published,1,6 as well as a small
number of publications7,8 discussing the SAR of PXR transactiva-
tion, but the flexibility of the receptor makes it very difficult to
extrapolate SAR to structurally different classes of compounds.
The common element of all published SAR of hPXR is a H-bond
acceptor in the center of the ligand, which according to Ref. 9 binds
to Gln285 and is indispensible for activation, combined with at least
2 (if aromatic) or 3 (if aliphatic), possibly up to 5, lipophilic fea-
tures, which are not essential for receptor activation but contribute
to ligand affinity.4,9
As part of ongoing research10–15 towards an ATP competitive
small molecule inhibitor of IGF-1R kinase16–20 the PXR transactiva-
tion of over 400 compounds within the benzimidazole-pyridone
chemotype was measured. The following discussion presents the
SAR observations from this effort, which led to the discovery of
compounds which inhibit IGF-1R, have in vivo activity and do
not transactivate PXR (Fig. 1).
One of the limitations of our first generation IGF-1R inhibitors
(e.g., compound 1) is their strong PXR transactivation.10,11 In an at-
tempt to reduce PXR transactivation and CYP450 inhibition while
* Corresponding author. Tel: +1 203 6777236; fax: +1 203 6777884.
E-mail addresses: Kurt.Zimmermann@bms.com, kzimmermann12@comcast.net
(K. Zimmermann).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.087

K. Zimmermann et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1744–1748
1745
Table 2
O
O
O
O
O
H
N
H
N
IGF-1R kinase, log D and PXR data of compounds 3a–j
N
N
N
NH
NH
Cmpd
R2
R3
R4
IGFa (nM)
Log Db
PXRc (%)
N
N
HN
HN
3a
3b
3c
3d
3e
3f
3g
3h
3i
Cl
H
H
H
H
H
H
H
H
H
Me
iPr
Et
Me
Me
iPr
CH2CH2OMe
Et
Cl
Cl
Cl
Br
Cl
H
Cl
H
H
160
360
83
75
38
360
290
480
190
550
1.87
1.62
1.27
0.80
0.74
0.60
0.54
0.28
65
52
27
14
25
5
18
5
2
HO
1
3
2
4
N
Cl
N
R1
O
H
N
NH
N
H
O
R5
N
N
NH
N
Me
CH2CH2OMe
À0.22
HN
3j
H
À0.33
4
HN
a
IGF-1R Kinase IC50
.
HO
b
R4
ACD Log D (pH 7.4) values were calculated using ACD/Log D Sol Suite 7.0,
R2
N
Advanced Chemistry Development, Inc., Toronto, ON, Canada, www.acdlabs.com
Cl
R3
2003.
c
% Transactivation of PXR receptor, compared to Rifampicin at 10
centration. See also Ref. 21.
lmol/l con-
Figure 1. General structure of compounds 1–4.
maintaining potency against IGF-1R kinase and oral exposure the
lipophilic m-chlorophenyl group of 1 was replaced with heteroar-
omatic groups. This led to the synthesis of compounds 2a–k and
3a–j.12 Within the series of C4-substituted pyrazoles 2a–k increas-
ing polarity (decreasing log D) correlates with a significant reduc-
tion of PXR transactivation (see Table 1 and Fig. 2) log D at pH
6.5, log D at pH 7.4 and clog P correlate equally well with PXR data,
but polar surface area does not.
These log D versus PXR data within two narrowly defined series
2a–k and 3a–j show the same trend as originally described by Gao
et al.,4 in that the introduction of polarity in the periphery of the
molecule reduces transactivation of PXR. It is noteworthy that
the correlation between log D and PXR does not hold true across
different chemical series (e.g., compounds 2a and 3a).
In these two series of compounds, exposed polarity strongly re-
duces oral exposure. While no compound combines the desired
IGF-1R kinase potency with reduced PXR transactivation and suffi-
cient oral exposure, the following observations are noteworthy.
The chloropyrazol-compound 2a has reduced protein binding
(compared to 1) and a remarkably high oral exposure (measured
as area-under-the-curve of drug concentration in plasma over time
after an oral dose of 20 mg/kg to mice, see Table 4). And among the
imidazoles 3a–j the chloro-methyl-imidazol 3e appears to have the
best combination of IGF-1R kinase potency with acceptable oral
exposure and low protein binding (see Table 4).12
Subsequently, as an alternative approach to address CYP and
PXR issues, variation of the left hand side of the molecule was also
explored. The morpholine of 1 was replaced with more polar and
larger groups, in an attempt to reduce CYP3A4 inhibition and
PXR transactivation while maintaining IGF-1R kinase potency and
oral exposure.13,14 Introduction of a polar basic amine functionality
in this portion of the molecule resulted in compounds with re-
duced CYP inhibition but also drastically reduced oral exposure.
Polar non-basic groups showed less reduction of CYP3A4 inhibition
but maintained better oral exposure.13,14
The same trend was observed within a series of substituted imi-
dazoles 3a–j.12 Increased lipophilicity of the substituents (higher
log D) led to an increase in PXR transactivation (Table 2 and Fig. 2).
Table 1
IGF-1R kinase, log D and PXR data of compounds 2a–k
Cmpd
R1
IGF-1Ra (nM)
Log Db
PXRc (%)
2a
2b
2c
2d
2e
2f
2g
2h
2i
Cl
COOEt
CH3
120
68
110
330
91
680
920
2060
1300
1550
5210
1.11
1.02
0.97
0.51
0.49
À0.02
À0.67
À0.85
À0.97
À1.27
À2.31
147
71
16
16
51
8
5
2
4
8
H
COOMe
CN
CH2OH
CONHMe
CONH2
CONMe2
COOH
2j
2k
6
a
IGF-1R Kinase IC50
.
b
ACD Log D (pH 7.4) values were calculated using ACD/Log D Sol Suite 7.0,
Advanced Chemistry Development, Inc., Toronto, ON, Canada, www.acdlabs.com
Most dramatically, replacing the morpholine of compound 1
with piperazine (4a) resulted in complete loss of PXR transactiva-
tion (see Table 3). Burying the polarity by N-methylating the piper-
azine (4b) brings back some PXR transactivation (24%), and the less
basic, more sterically hindered fluoroethyl-amine 4c is as strong a
PXR transactivator as the morpholine 1. Within this limited series
lower PXR transactivation correlates with less CYP3A4 inhibition.
The basic terminal nitrogen of compounds 4a–c is almost fixed
in space, does not have the flexibility to seek a favorable interac-
tion with a ligand binding site. Rotation around the bond between
C6 of the benzimidazole and the proximal piperazine nitrogen does
not alter the position of the distal piperazine nitrogen. In contrast,
the basic nitrogen of the closely related amino-pyrrolidines 4d and
4e can access different regions of the PXR ligand binding site and
both enantiomers are much stronger PXR transactivators then 4a
and 4b. The same observation is repeated comparing the carba-
mates 4f and 4g. The more flexible, non-linear N-BOC-aminopyr-
rolidine 4g can find a favorable interaction with the hPXR protein
or avoid a steric constraint, and therefore transactivates much
stronger (55%) then the straight, less flexible but equally polar N-
2003.
c
% Transactivation of PXR receptor, compared to Rifampicin at 10
centration. See also Ref. 21.
l
mol/l con-
160
140
120
100
80
60
40
Pyrazoles 2a-k
Imidazoles 3a-j
20
0
-3.0
-2.0
-1.0
0.0
1.0
2.0
LogD (pH=7.4)
Figure 2. PXR transactivation as a function of log D for compounds 2a–k and 3a–j.
Graphical representation of data from Tables 1 and 2.

1746
K. Zimmermann et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1744–1748
Table 3
BOC-aminopiperidine 4f (0%). The corresponding amides (e.g., 4h)
also do not transactivate hPXR, despite being strong CYP3A4
inhibitors.
IGF-1R kinase, CYP3A4 and PXR data of compounds 1, 4a–l
Cmpd
R5
IGFa (nM)
CYPb
(lM)
PXRc (%)
In an attempt to balance oral exposure with reduced CYP3A4
inhibition,13 bicyclic substituents with a moderately basic amine
nitrogen were explored (e.g., compounds 4i–k). None of these com-
pounds have significant PXR transactivation. The less polar, non-
basic spiroketal 4l, with it’s two rings orthogonal, is a strong PXR
transactivator, confirming that size alone is not the reason why
4f and 4h–k do not transactivate hPXR.
These data suggest (in agreement with Ref. 4) that this pocket of
the ligand binding site of hPXR prefers lipophilic substituents but
can accommodate polar substituents if they have sufficient rota-
tional freedom to find a favorable interaction with one of the eight
polar amino acids in the binding site. In contrast, the binding (and
the required de-solvation) of polar rigid substituents is energeti-
cally unfavorable. [An alternative explanation is that the corre-
sponding PXR + ligand complex forms but does not transactivate.]
PXR transactivation data for the more diverse compounds 1, 4a–
l in Table 3 (compared to Tables 1 and 2) do not show an obvious
correlation with calculated hydrophobicity nor with CYP inhibition
data, in agreement with Redinbo’s observation that PXR ligands do
not cluster in a particular clog P region2 (Fig. 3).
Several of the above compounds have promising pharmacoki-
netic properties (reduced CYP3A4 inhibition, reduced PXR transac-
tivation or good oral exposure; see Refs. 10–14) but none of them
combines all the required properties with the required IGF-1R
kinase potency.
The next logical step was to combine the polar and rigid ‘left
hand pieces’ of compounds that do not transactivate PXR (e.g., 4i,
4k) with the pyrazolylethyl- and imidazolylethyl-side chains of
compounds 2a and 3e that had shown reduced protein binding
and sufficient oral exposure.
1
100
32
0.5
3.0
3.5
90–123
O
N
4a
4b
1
HN
N
18
24
N
F
N
4c
4d
4e
32
71
42
0.8
18.0
>4.4
120
113
44
N
N
H2N
H2N
N
N
O
O
N
N
4f
330
16
0
O
N
H
H
O
N
4g
4h
410
50
>13
0.7
55
1
HN
O
N
4i
4j
45
29
1.7
0.5
3
2
O
O
N
N
N
N
O
N
N
N
4k
4l
82
75
3.5
0.7
1
O
O
N
102
O
a
IGF-1R Kinase IC50
.
b
CYP3A4 inhibition, 7-benzyloxy-4-trifluoromethylcoumarin was used as probe
As reported previously for compound 4k,13 formally replacing
the morpholine group of compounds 2a and 3e with the bicyclic
carbamate fragment to make compounds 5 and 6 (see Fig. 4 and
Table 4) does not negatively impact the kinase or cell potency
against the engineered IGF-Sal cell line.15 The chloro-pyrazole
compounds (2a and 5) show lower kinase inhibition (higher
IC50’s) and higher protein binding then the corresponding chloro-
imidazoles (3e and 6), but significantly better oral exposure. Their
potency in the IGF-Sal cell proliferation assay is identical within
the accuracy of the assay. The large, hydrophilic and non-flexible
piperazino-piperidine substituent (as shown above for 4k) elimi-
nates hPXR transactivation of 5 and 6.
molecule.
c
% Transactivation of PXR receptor, compared to Rifampicin at 10
centration. See also Ref. 21.
lmol/l con-
140
120
100
80
60
40
One of the limitations of the earlier compounds is their high
protein binding (>99% for 1). Replacing the phenethylamine frag-
ment of compound 1 with heteroarylethylamines significantly in-
creased the free fraction of compounds 2a and 3e in human
plasma to 1.7% and 5.9%, respectively.12 Protein binding is gener-
ally lower for the piperazino-piperidines 4k, 5, 6 (compared to
20
0
0.0
1.0
2.0
3.0
4.0
5.0
LogD (pH=7.4)
Figure 3. PXR transactivation as a function of log D for compounds 1, 4a–l.
Table 4
IGF-1R kinase IC50s of compounds 1, 2a, 3e, 4k, 5 and 6, cell potency and selected pharmacokinetic data
Compd
IGF-1Ra (nM)
IGF-Salb (nM)
CYP 3A4c
(l
M)
PXR%TAd
AUCe
(l
M h)
%PBf
99.6
98.3
94.1
>98
96.7
89.0
1
100
120
38
82
86
110
376
336
77
279
222
0.5
2.1
1.9
3.5
1.0
0.7
90–123
51
90
8.2
11
52
48
2a
3e
4k
5
147
25
1
1
1
6
19
a
b
c
d
e
f
IGF-1R Kinase IC50
.
Cellular IC50, measured via thymidine incorporation.
CYP3A4 inhibition, 7-benzyloxy-4-trifluoromethylcoumarin was used as probe molecule.
% Transactivation of PXR receptor, compared to Rifampicin at 10 mol/l concentration. See also Ref. 21.
Area under the curve for plasma concentration of compound versus time, interval 0–4 h, after oral administration of 20 mg/kg to mice.
% Protein binding in human plasma.
l

K. Zimmermann et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1744–1748
1747
H
N
O
Boc
H
N
O
N
R
R
NH
NH
N
N
O
X
H
N
N
N
N
N
NH
HN
HN
N
12
Cl
N
5
6
N
N
N
X=Cl, I
Cl
a, b, c
O
O
N
O
O
R =
N
N
N
O
H
N
NH
Figure 4. Structures of compounds 5 and 6.
N
5-6
HN
R
morpholine-analogs 1, 2a, and 3e) and within this series, the same
trend can be seen as described above. The phenethylamine 4k has a
free (unbound) fraction of ꢀ1–2%, whereas the heteroaryl analogs
5 and 6 have unbound fractions of 3.3% and 11%, respectively (see
Table 4). This significant improvement in protein binding
warranted further in vivo studies.
NH2
NH2
RNH2
=
N
N
N
Cl
N
Cl
Drug concentration in plasma (measured as area-under-the-
curve of drug concentration in plasma over time after an oral dose
of 20 mg/kg to mice) was found to be moderate for compound 4k
(see Table 4) and high for compounds 5 and 6, despite the high
molecular weight of these compounds (620, 594, and 608 Da,
respectively).
Finally, compounds 5 and 6 were evaluated in different mouse
tumor xenograft models. While both compounds 5 and 6 showed
ꢀ100% tumor growth inhibition23 (TGI) at 100 mg/kg dosed once
a day for 14 days in the constitutively activated IGF-Sal tumor
model,15 only compound 6 inhibited tumor growth at 50 mg/kg
(65% TGI), whereas 5 (30% TGI) was not efficacious at this lower
dose.
for 5
for 6
Scheme 2. Synthesis of compounds 5 and 6. Reagents and conditions: (a) RNH2,
Huenig’s base, CH3CN, 80 °C 16 h, 75%; (b) CF3COOH, CH2Cl2, 20 °C; (c) CH3OCOCl,
Huenig’s base, MeOH, 0–20 °C, ꢀ80%.
Efficacy was also observed in the Colo205 human colon carci-
noma model. Compounds 5 and 6 are both active at 100 mg/kg
qd dosing, compound 6 is also active at 50 mg/kg. The less sensitive
GEO human colon carcinoma model showed a moderate response
(ꢀ60% TGI) for both compounds 5 and 6 at 100 mg/kg on a
QD Â 14 day dose schedule, whereas 200 mg/kg doses of both
compounds are toxic.
Conclusions: In summary, we report two in vivo active IGF-1R
inhibitors (compounds 5 and 6) and discuss a successful SAR opti-
mization strategy away from PXR transactivation, which we expect
to be of general interest to many medicinal chemists.
NH2
NH2
NH2
Further studies of compounds 5 and 6 led to the discovery that
both compounds, despite not showing significant PXR transactiva-
tion still induce CYP3A4 mRNA in human hepatocytes. Further
studies into the mechanism of this non-PXR induction are under-
way and will be published soon.
N
N
O
a
b, c, d
N N
N N
O
O
OH
OH
7
8
9
Chemistry: The syntheses of compounds 1,10 2a–f,12 3a–j,12 4a–
c,14 4f,13 and 4h–l13 have been described in our previous publica-
tions. Compounds 2g–k are available from 712 via borane reduction
(for 2g) or ester saponification (for 2k) and amide bond formation
(for 2h–j), followed by SNAr reaction with 11 (Scheme 1).12
Compounds 4d, 4e, and 4g were easily accessed following the
synthetic route as described for 4f,13 using commercially available
3-BOC-aminopyrrolidine. The synthesis of compounds 5 and 6 fol-
lowed the route shown in Scheme 2. Intermediate 1213 was reacted
with the heteroarylethylamine components12 in acetonitrile at
80 °C. Cleavage of the BOC protecting group and methyl carbamate
formation following standard methods gave access to the target
compounds in high yields.
NH2
N N
O
NR1R2
10a-c
O
O
N
N
8 9 10a-c
or
,
NH
N
O
NH
f
Acknowledgement
N
O
HN
NH
X
NH
N
The authors thank the lead profiling department at Bristol-
Myers Squibb for generating the data presented in Tables 1–4.
2g R=CH2OH
2h R=CONHMe
2i R=CONH2
2j R=CONMe2
2k R=COOH
N
X=Cl, I
R
11
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HCl/dioxane, 1 h, 20 °C; (e) EDC, HOBt, NR1R2H, 18 h, 20 °C; (f) amine 8, 9 or 10,
Huenig’s base, DMSO, 80 °C 16 h.

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23. %TGI = (tumor size of control group at end of treatment) À (tumor size of
treated group at the end of treatment)/(tumor size of control group at end of
treatment) À (tumor size of control group at the start of treatment). %TGI >50%
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