Structure-based design, SAR analysis and antitumor activity of PI3K/mTOR dual inhibitors from 4-methylpyridopyrimidinone series

Article abstract of DOI:10.1016/j.bmcl.2013.02.020

PI3K, AKT and mTOR, key kinases from a frequently dysregulated PI3K signaling pathway, have been extensively pursued to treat a variety of cancers in oncology. Clinical trials of PF-04691502, a highly potent and selective ATP competitive kinase inhibitor of class 1 PI3Ks and mTOR, from 4-methylpyridopyrimidinone series, led to the discovery of a metabolite with a terminal carboxylic acid, PF-06465603. This paper discusses structure-based drug design, SAR and antitumor activity of the MPP derivatives with a terminal alcohol, a carboxylic acid or a carboxyl amide.

Full text of DOI:10.1016/j.bmcl.2013.02.020

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2787–2792
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure-based design, SAR analysis and antitumor activity of PI3K/
mTOR dual inhibitors from 4-methylpyridopyrimidinone series
a
a
a
a
a
Hengmiao Cheng a, , Jacqui E. Hoffman , Phuong T. Le , Mason Pairish , Robert Kania , William Farrell ,
Shubha Bagrodia b, Jing Yuan b, Shaoxian Sun b, Eric Zhang c, Cathy Xiang c, Deepak Dalvie c,
Sadayappan V. Rahavendran c
⇑
a Cancer Chemistry, Pfizer Worldwide Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA, 92121, USA
b Oncology Research Unit, Pfizer Worldwide Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA, 92121, USA
c PDM, Pfizer Worldwide Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
PI3K, AKT and mTOR, key kinases from a frequently dysregulated PI3K signaling pathway, have been
extensively pursued to treat a variety of cancers in oncology. Clinical trials of PF-04691502, a highly
potent and selective ATP competitive kinase inhibitor of class 1 PI3Ks and mTOR, from 4-methylpyrido-
pyrimidinone series, led to the discovery of a metabolite with a terminal carboxylic acid, PF-06465603.
This paper discusses structure-based drug design, SAR and antitumor activity of the MPP derivatives with
a terminal alcohol, a carboxylic acid or a carboxyl amide.
Received 15 December 2012
Revised 23 January 2013
Accepted 1 February 2013
Available online 13 February 2013
Keywords:
SBDD
Ó 2013 Elsevier Ltd. All rights reserved.
Kinase inhibitor
PI3K/mTOR dual inhibitor
Cancer
Antitumor
Effective polar surface area
ePSA
Metabolite
The phosphatidylinositol 3-kinase (PI3K) signaling pathway
plays crucial roles in cell growth, proliferation and survival, and
is a frequently dysregulated pathway in human cancers.1,2 Inhibi-
tors of key kinases in the pathway, including PI3K, AKT and mTOR,
have been extensively pursued in oncology in recent years.3 In or-
der to effectively block the PI3K pathway, overcome feedback
loops,4 and block PI3K independent mTOR activation, our strategy
to target PI3K signaling pathway is focused on pursuing PI3K/
mTOR dual inhibitors. PF-04691502 is a highly potent and selective
ATP competitive kinase inhibitor of class 1 PI3Ks and mTOR, and
has progressed to phase I/II clinical trials for the treatment of solid
tumors (see Fig. 1).5,6
formed key hydrogen bonds with the hinge residue, Val 882. The
methyl at the 4 position on the MPP core fit tightly in a small hydro-
phobic pocket unique to PI3K and mTOR, conferring excellent ki-
nase selectivity for the MPP derivatives. The ring nitrogen on the
methoxypyridine formed a key hydrogen bond with a conserved
water molecule in the selectivity pocket. The terminal alcohol of
the hydroxyethyl formed an intramolecular H bond with the ether
oxygen atom off the cyclohexyl ring, reducing the effective number
of hydrogen bond donors, and helping the compound to achieve
excellent permeability and cellular potency.
Structural analysis also revealed that the terminal alcohol was
located in a solvent exposed region surrounded by polar residues,
and there was space between the terminal alcohol and the polar
PF-04691502, derived from 4-methylpyridopyrimidinone (MPP)
series, exhibited potent in vitro activity against class I PI3K isoforms
residues. Modeling studies, exemplified by docking 29 in PI3K
c
and mTOR, with mPI3K
surrogate of human PI3K
a
Ki of 0.57 nM (mouse PI3K
a
was used as a
as illustrated in Figure 3, indicated a primary carboxyl amide
would fit in the space, with the amide carbonyl pointing towards
the solvent, and an intramolecular H bond between the amide
N–H and the ether oxygen could be formed. In PF-04691502 co
a
in the primary screening), and mTOR Ki
of 16 nM. In a BT20 cell assay, measuring inhibition of AKT phos-
phorylation at S473, PF-04691502 exhibited excellent cellular po-
tency with an IC50 of 13 nM. Co crystal structure of PF-04691502
crystal structure with PI3Kc, the Lys 833 side chain was pointing
bound in PI3K
c
was determined (Fig. 2).5 The aminopyrimidine
down as shown in Figure 2, and there was no H bond interaction
between MeO-pyridine and Lys 833. However, the F atom on the
4-MeO-5-F-3-pyridine in 29 pushed Lys 833 up and inward as
illustrated in Figure 3, the terminal amino group from Lys 833 side
⇑
Corresponding author.
E-mail address: henry.cheng@pfizer.com (H. Cheng).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.02.020

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H. Cheng et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2787–2792
CH3
chain was in close distance to form H bonds with both the oxygen
atom and the F atom. The H bond interaction between the
conserved water molecule and the pyridine ring N was retained.
The interaction between 4-MeO-5-F-3-pyridine and Lys 833 and
the conserved water molecule was recently reported both for a
modified MPP derivative7 and for AMG 511, in which 4-MeO-5-F-
3-pyridine was attached to a different scaffold.8 Based on the mod-
eling studies, we decided to investigate the SAR by replacing 4-
MeO-3-pyridine in PF-04691502 with different heteroaryl groups
including 4-MeO-5-F-3-pyridine. In addition, the terminal amide
derivatives had much higher Topological Polar Surface Area (PSA)
than the terminal alcohol derivatives such as PF-04691502, so we
were interested in comparing the SAR between the amides and the
O
CH3
N
N
N
H2N
N
O
O
HO
PF-04691502
alcohols, for example, binding affinities with mPI3K
a and mTOR,
Figure 1. Chemical structure of PF-04691502.
correlation between PSA, LogD, permeability and cellular potency.
Illustrated in Scheme 1 is the synthetic route for preparing MPP
derivatives with cis-cyclohexyl moiety substituted at the 8 posi-
tion; the trans-cyclohexyl derivatives were prepared by using the
corresponding trans-4-aminocyclohexanol at step 1.9 Compound
1 was reacted with cis-4-aminocyclohexanol to produce compound
2, which was reacted with tert-butyl bromoacetate, followed by
quenching with MeOH to give the isolated methyl ester 3. The ester
in 3 was reacted with ammonia to yield compound 4, which was
reacted with hydroxylamine in ethanol to generate compound 5.
Palladium-catalyzed coupling of 5 with ethyl acrylate yielded com-
pound 6, which was subjected to intramolecular cyclization to gen-
erate compound 7. Bromination of 7 with NBS, followed by Suzuki
coupling reactions with an appropriate bronic acid or bronic ester
gave the desired product 9.
To assess the metabolic profile of PF-04691502 in humans
in vivo, the plasma obtained from patients dosed with PF-
04691502 at 8 mg QD in a clinical pharmacology dose escalation
study was analyzed.10 The high dose was selected for metabolite
profiling to ensure that all metabolites were detected in the human
plasma. The total ion chromatogram of plasma showed 4 peaks.
The retention times and the molecular ions of the peaks at 24.81
and 26.80 min were identical to the PF-0444794911 and unchanged
PF-04691502, respectively (Fig. 4). The additional peaks at
25.24 min (M2) and 29.07 (M6) showed molecular ions at m/z
602.2 and 440.19. The fragmentation pattern of the two molecular
ions suggested the M2 and M6 were the glucuronide conjugate of
PF-04691502 and the carboxylic acid metabolite, respectively
(Fig. 5). Although the site of conjugation was unknown, the forma-
tion of M2 involved catalysis by uridine glucuronyl transferase
(UGT). On the other hand, the formation of M6 was mediated by
oxidation of the alcohol either by CYP450 or via alcohol dehydro-
genase to the aldehyde that was oxidized to the corresponding
acid, ({trans-4-[2-amino-6-(6-methoxypyridin-3-yl)-4-methyl-7-
oxopyrido[2,3-d]pyrimidin-8(7H)-yl]cyclohexyl}oxy)acetic acid (M6,
PF-06465603) (Scheme 2). The identity of M6 was further con-
firmed by comparison of its mass spectrum and retention time
with an authentic standard, which was prepared from PF-
04691502 by oxidizing the primary alcohol to the acid (Scheme 3)
MPP derivatives with different heteroaryl groups off the 6 posi-
tion, with cis or trans-cyclohexyl off the 8 position, and with termi-
nal alcohol or terminal amide were prepared following the
synthetic route described in Scheme 1. The in vitro potency, calcu-
lated SFLogD, HLM in vitro clearance, permeability (RRCK), and PSA
for the alcohol and amide derivatives, and the metabolite 10 are
summarized in Table 1.
Figure 2. Co crystal structure of PF-04691502 bound in PI3Kc.
In the mPI3Ka assay, compounds with six-membered heterocy-
cle are in general more potent than those with 5 or 10-membered
heterocycles as shown in Figure 6, suggesting six-membered het-
erocycle fits the best in PI3Ka binding site. Modeling studies with
29 indicated that the F atom could help position Lys 833 side chain
Figure 3. Amide derivative 29 modeled in PI3K
c
.
to form H bonds with both the oxygen atom and the F atom of the

H. Cheng et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2787–2792
2789
CH3
Br
CH3
N
CH3
N
Br
CH3
N
N
Br
Cl
CH3
N
N
CH3
N
N
N
NH
NH
Step 1
Step 2
CH3
CH3
CH3
2
3
1
O
OH
O
CH3
O
O
O
CH3
N
CH3
CH3
N
Br
Br
CH3
N
N
N
CH3
N
NH
H2N
N
N
O
H2N
NH
Step 4
Step 3
CH3
Step 5
O
4
O
O
5
O
6
O
NH2
NH2
NH2
CH3
N
CH3
N
CH3
N
Br
O
N
R
N
N
H2N
N
O
O
H2N
N
O
H2N
N
O
Step 8
Step 7
Step 6
O
O
O
7
9
NH2
O
8
NH2
NH2
Scheme 1. Synthesis of amide derivatives. Reagents and conditions: (1) cis-4-aminocyclohexanol, diisopropylethylamine, DMF, yield: 82%; (2) (a) tert-butyl bromoacetate,
NaH, THF, (b) MeOH, yield: 37%; (3) ammonia in methanol; (4) NH2OH hydrochloride, EtOH/water, reflux, yield: 50% over two steps; (5) ethyl acrylate, Pd(PPh3)4,
triethylamine, yield: 69%; (6) PhSH, NsAPh, DBU, DIEA, yield: 89%; (7) NBS, DMF, yield: 97%; (8) boronic acid, K2CO3, Pd(PPh3)2Cl2, DMF–water.
26.80
1.4e6
1.4e6
Max. 1.4e6 cps.
PF4691502
1.3e6
1.2e6
1.1e6
1.0e6
9.0e5
8.0e5
7.0e5
6.0e5
5.0e5
4.0e5
3.0e5
2.0e5
1.0e5
0.0
M4
24.81
M6
29.07
M2
25.24
M1034.85
16.65
18.89
19.91
14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Time, min
Figure 4. TIC of PF-04691502 and metabolites from FIP plasma sample.
4-MeO-5-F-3-pridine, hence increasing binding affinity. Indeed, 29
exhibits significant increase in mPI3K Ki over the corresponding
With regarding to physical properties, compounds discussed in
the manuscript exhibit a wide range of calculated SFLogD (À0.35 to
2.65) and PSA (116–161). All the compounds, except the cis-cyclo-
hexyl alcohols, are stable to in vitro oxidative clearance in HLM
a
des-F compound 28. In an mTOR kinase assay, compounds with
six-membered heterocycles such as 13 and 22 exhibit potent Ki.
Interestingly, the most potent compound from the mTOR assay,
19, has a pyrazole substituted at 6 position. When the pyrazole is
methylated, the resultant compound 20 exhibits ninefold decrease
in mTOR Ki, suggesting that the pyrazole N–H in 19 forms a H bond
in the mTOR binding site. The lack of crystal structure of mTOR
complex makes it difficult to explain the observed SAR at the
molecular level. Figure 6 also shows there is no correlation be-
clearance studies, with Clint <8
alcohol and amide derivatives is plotted against mPI3K
Ki, PSA, RRCK, or calculated SFLogD, correlation is only seen be-
tween Cell IC50 and mPI3K Ki, as illustrated in Figure 7. Both
l
l/min/mg. When cell IC50 for both
a
Ki, mTOR
a
trans-cyclohexyl alcohol 17 and trans cyclohexyl amide 29, with
4-MeO-5-F-3-pyridine at 6 position, exhibit excellent cell potency,
with IC50 of 5.24 and 5.82 nM, respectively. The metabolite 10
tween mPI3K
a
Ki and mTOR Ki.
demonstrates potent Ki against mPI3Ka and mTOR, however, it

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H. Cheng et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2787–2792
N
O
HO
HO
N
O
CO2H
CH3
N
CH3
N
O
CH3
CH3
CH3
N
CH3
O
N
N
HO
N
H2N
N
O
O
H2N
N
N
O
O
H2N
N
O
O
O
HO
HO
HO
PF-04691502
M2
PF-06465603 (M6)
N
O
CH3
CH3
N
H2N
N
N
O
PF-04447949 (M4)
OH
Figure 5. Metabolites identified from FIP day 21 plasma samples.
CH3
O
CH3
O
CH3
O
N
N
N
CH3
N
CH3
CH3
N
N
N
N
P450
H2N
N
O
O
P450
H2N
N
N
O
O
H2N
N
O
O
Or
Or
Alcohol
Aldehyde
Dehydrogenase
Dehydrogenase
OHC
HO2C
HO
Scheme 2. Proposed pathway for the formation of the carboxylic acid metabolite (PF-06465603).
N
O
N
O
CH3
N
CH3
Tempo/NaOCl
CH3
N
CH3
N
N
NaOCl2
H2N
N
O
O
H2N
N
O
O
O
80%
OH
OH
PF-04691502
10 (PF-06465603)
Scheme 3. Synthesis of 10 (PF-06465603).
exhibits weak cell potency with IC50 of 2.07
l
M. At physiological
terminal amide. Farwell developed a method to measure the effec-
tive polar surface area (ePSA), which measures the exposed polar-
ity of a molecule in a non-polar environment, and is reflective of
both the intramolecular H bond and the size of molecules.12 ePSA
was determined for 13 compounds from Table 2, including both
terminal alcohol and terminal amide derivatives. Even though
there is no direct correlation between ePSA and PSA as illustrated
in Figure 8, formation of intramolecular H bond can significantly
reduce the effective polar surface area. Several compounds, with
PSA greater than 135 Å, exhibits ePSA between 82 and 101 Å,
which is a range capable of yielding excellent permeability and
cellular potency. This suggests that, for designs with high PSA,
pH, its terminal carboxylic acid is deprotonated, unable to form
the corresponding intramolecular H bond that is present in the
alcohol and the amide derivatives, therefore exhibiting poor per-
meability, with RRCK value of 0.295 Â 10À6 cm/s, and weak cell
potency.
Figure 7 illustrates that there is no correlation between cell IC50
and PSA for the compounds discussed in this paper; some com-
pounds with high PSA exhibits excellent cellular activity. For
example, PSA for 29 is 148 Å, and cell IC50 is 5.82 nM. This can be
explained by the formation of the intramolecular H bond between
the ether oxygen atom off the cyclohexyl and the N–H from the

H. Cheng et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2787–2792
2791
Table 1
SAR summary for MPP derivatives
CH3
R2
N
H2N
N
N
O
O
R1
cis/transa
R1
R2
mPI3Ka Kib
(nM)
mTOR Kib
(nM)
Cellb IC50
(nM)
cSFLogD
HLM Clint
l/min/mg)
RRCK
TPSA
ePSAc
(
l
(10À6 cm/s)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
trans
cis
cis
cis
cis
–COOH
–OH
–OH
–OH
–OH
–OH
–OH
–OH
–OH
4-MeO-3-pyridine
4-MeO-3-pyridine
4-MeO-5-F-3-pyridine
4-MeO-3-pyrimidine
3-Pyrazole
3-Me-3-pyrazole
3-Quinoline
4-MeO-5-F-3-pyridine
4-MeO-3-pyrimidine
3-Pyrazole
3-Me-3-pyrazole
3-Quinoline
4-MeO-3-pyridine
4-MeO-5-F-3-pyridine
4-MeO-3-pyrimidine
3-Pyrazole
3-Me-3-pyrazole
3-Quinoline
4-MeO-3-pyridine
4-MeO-5-F-3-pyridine
4-MeO-3-pyrimidine
3-Pyrazole
0.350
4.51
1.18
2.41
13.5
26.4
24.1
0.654
1.00
3.44
10.1
8.01
1.67
0.700
1.82
6.89
24.8
7.41
1.91
0.312
1.82
6.16
21.8
5.74
8.63
12.8
ND
2070
21.6
ND
À0.347
2.3
<8.00
55.7
142
18
23.4
13.3
105
<8
<8
<8
<8
<8
<8
<8
<8
<8
<8
<8
<8
<8
0.295
19.3
17.9
142
125
125
138
132
121
116
125
138
132
121
116
148
148
161
155
144
139
148
148
161
155
144
139
99
77
76
82
95
78
88
2.44
1.47
1.42
1.43
2.65
2.44
1.47
1.42
1.43
2.65
1.67
1.9
0.991
1.33
0.942
2.38
1.67
1.9
4.46
7.50
45.9
10.7
24.4
5.05
2.15
19.5
7.82
2.54
45.4
12.6
4.52
92.6
48.0
29.5
11.1
8.80
29.4
11.2
310
104
5.24
22.0
25.9
288
23.8
23.3
8.22
82.9
148
988
116
19.3
5.82
51.9
256
376
56.8
12.6
23.3
41.6
cis
cis
trans
trans
trans
trans
trans
cis
cis
cis
cis
cis
21.3
87
101
–OH
–OH
–OH
19.7
30.3
26.2
30.1
0.151
–CONH2
–CONH2
–CONH2
–CONH2
–CONH2
–CONH2
–CONH2
–CONH2
–CONH2
–CONH2
–CONH2
–CONH2
85
85
cis
4.57
4.58
26.2
29.8
97
trans
trans
trans
trans
trans
trans
0.991
1.3311
0.942
2.28
<8
3-Me-3-pyrazole
3-Quinoline
9.10
<8
9.02
101
a
b
c
Relative sterochemistry of the two substituents on cyclohexyl.
Inhibition constants (Ki) and cell IC50 were determined as described in Refs. 5,6. The coefficients of variance were typically less than 20% (n = 2).
Effective polar surface area.12
Figure 6. mPI3K
a
Ki versus mTOR Ki plot.
Figure 7. Correlation between S473 Cell IC50 versus mPI3Ka Ki.
introduction of an intramolecular H bond can help achieve good
permeability and cellular potency by modulating ePSA to a desir-
able range.
Compound 17, exhibiting excellent overall properties such as
very good in vitro potency and low HLM clearance, was progressed
to in vivo experiments including rat PK and mouse xenograft tumor
growth inhibition efficacy studies. Compound 17 demonstrated
excellent rat PK profile, with clearance of 17.0 ml/min/kg, Vdss of
4.08 L/kg, T1/2 of 2.77 h, and 79% oral bioavailability. In TGI studies,
17 exhibited dose dependent efficacy in U87 xenograft model, dem-
onstrating 89% TGI at the MTD of 10 mg/kg (Fig. 9).6 Figure 10
shows that a robust in vivo PK/PD correlation for 17 was observed
for samples from the high dose treatment group in the TGI studies.
At 1 h time pint, high free drug concentration in plasma yielded

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H. Cheng et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2787–2792
maximum inhibition of AKT phosphorylation. At 24 h time point,
very low free drug concentration in plasma was correlated with
minimum inhibition of AKT phosphorylation.
In summary, the MPP derivatives, including PF-06465603, a
metabolite from human clinical trial of PF-04691502, demon-
strated potent Ki in both mPI3Ka and mTOR in vitro assays. Even
though calculated PSA was very high for the terminal alcohol and
terminal amide MPP derivatives, the formation of the intramolec-
ular H bond helped them to exhibit ePSA in a range to achieve good
permeability and good cellular activity. Compound 17 (PF-
04691503),13 demonstrating excellent in vitro potency and robust
ADMET properties, was progressed to in vivo antitumor efficacy
model, and exhibited robust tumor growth inhibition.
Acknowledgments
John Almaden, Tom Carlson, Hieu Lam, Jeff Wang, Peter Wells,
and Aihua Zou are acknowledged for biochemical screenings. Jef-
frey Chen, Jon Engebretsen, and John Li are acknowledged for cel-
lular screening. Jason Zbieg is acknowledged for synthesis
assistance.
Figure 8. Correlation between PSA and ePSA.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.02.
020.
2000
1500
1000
500
0
Vehicle
1mg/kg
3mg/kg
10mg/kg
References and notes
46%***
52%***
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10 11
1
2
3
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Days postdose
Figure 9. Tumor growth inhibition by 17 in U87MG mouse xenograft model (ÃÃÃ
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120%
100%
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60%
40%
20%
0%
200
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100
50
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S.; Le, P. T. Q.; Nambu, M. D.; Pairish, M. A.; Plewe, M. B.; Tran, K. T. Pyrido (2,3)
pyrimidinone compounds and their use as PI3 inhibitors, WO 2008/032162.
10. Hamilton, R. A.; Garnett, W. R.; Kline, B. J. Clin. Pharmacol. Ther. 1981, 29, 408.
11. Biological activity for PF-04447949 was discussed in Ref. 5.
12. Farrell, W.; Masters-Moore, D.; Murphy, S.; Lafontaine, J. HPLC 2010
Symposium, Boston, MA, June 23, 2010, Oral Presentation. Manuscript
describing the ePSA protocol is in preparation by Farrell.
13. Berlinski, P.; Kamerling, S.; Colhoun, H.; Forester, N.; Marotti, K.; Bagrodia, S.;
Cheng, H.; Pascual, B.; Yuan, J.; Chen, J.; Engebretse, J.; Rafidi, K.; Zhang, E.;
Wang, S.; Zou, A.; Carlson, T.; Almaden, C.; Barker, J.; Gehring, M.; Nguyen, L.;
Shen, A.; Hemkens, M.; McHarg, A.; Sun, S.; Carley, W. 2010 AACR poster
abstract # 5043, Washington DC, USA.
0
1hr
7hr
24hr
Relative pAKT/AKT
Plasma Conc. [free nM)
Figure 10. PK/PD correlation for 17 dosed at 10 mg/kg.