Full text of DOI:10.1039/d0md00408a

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RESEARCH ARTICLE
Second-generation tricyclic pyrimido-pyrrolo-
oxazine mTOR inhibitor with predicted blood–
brain barrier permeability†
Cite this: RSC Med. Chem., 2021, 12,
579
a
Chiara Borsari, ‡a Erhan Keles, ‡a Andrea Treyer, b Martina De Pascale,
a
Paul Hebeisen,ac Matthias Hamburger b and Matthias P. Wymann
*
Received 4th December 2020,
Accepted 22nd December 2020
Highly selective mTOR inhibitors have been discovered through the exploration of the heteroaromatic ring
engaging the binding affinity region in mTOR kinase. Compound 11 showed predicted BBB permeability in
DOI: 10.1039/d0md00408a
a
MDCK-MDR1 permeability in vitro assay, being the first pyrimido-pyrrolo-oxazine with potential
rsc.li/medchem
application in the treatment of neurological disorders.
targeting both mTORC1 and mTORC2, including CC-223,7
INK128,8 AZD2014,9 PQR620,10 PQR626 (ref. 11) and
Introduction
a
The mechanistic target of rapamycin (mTOR) operates
downstream of phosphoinositide 3-kinase (PI3K). The mTOR
protein kinase is part of two functionally distinct multiprotein
mTOR complexes, mTORC1 and mTORC2.1,2 mTOR promotes
cell growth and proliferation and is dysregulated in cancer
and central nervous system (CNS) disorders,3 such as
Parkinson's, Alzheimer's, Huntington's disease, and epilepsy.4
Tuberous sclerosis complex (TSC) is a negative regulator of
TORC1. TSC loss-of-function causes hyperactivation of TORC1
signalling leading to the development of tuberous sclerosis,
which causes epilepsy, behavioural changes and cognitive
impairment in >90% of patients. Rapamycin is an allosteric
inhibitor of TORC1, and is the prototype of first generation
mTOR inhibitors. Everolimus, a rapalog, showed efficacy in
decreasing the frequency and severity of epileptic seizures
and has been approved for the treatment of TSC patients in
thiazolopyrimidine derivative.12 Recently, we have disclosed a
conformational restriction strategy to identify highly selective
TORKi.13 A systematic structure–activity relationship (SAR)
study pinpointed the pyrazine derivative 12b as potent
inhibitor of mTOR kinase (Ki = 8.0 nM), showing a 212-fold
selectivity over the structurally related PI3Kα (see Table 1 for
chemical structure).14 However, 12b displayed a limited ability
to cross the BBB, preventing its application in the treatment
of CNS disorders such as epilepsy. Given the unexplored
activity of the tricyclic pyrimido-pyrrolo-oxazine compounds
in CNS indications, we selected this privileged scaffold as
starting point for the development of novel lead compounds
with potential brain permeability.
Study design and synthesis
2018.5
Rapalogs
have,
however,
significant
Herein, we investigated the effect of the heteroaryl moiety,
engaging the binding affinity region in the mTOR kinase, on
ligand potency and brain penetration. In several compound
classes, isosterism between 6-membered diazaheterocycles
and thiadiazole derivatives has been exploited to improve
potency, enhance selectivity, alter physical properties, modify
and reduce metabolism.15 The introduction of fluorine into
molecular scaffolds16 is known to modulate lipophilicity, and
plays an important role in BBB permeability.
We explored different bioisosters, and difluoro/trifluoro-
substituted heteroaromatic rings on the tricyclic scaffold. The
synthetic procedures for library preparation are reported in
Schemes 1 and 2. Sulfamidate 22 was prepared starting from
a chiral amino alcohol – (S)-serine – in several steps (ESI† for
details).17,18 The tricyclic pyrimido-pyrrolo-oxazine scaffold
was generated by sequential alkylation and a nucleophilic
aromatic substitution reaction of dichloropyrimidine 12 with
immunosuppressive effects, which are pronounced due to
their limited ability to cross the blood brain barrier (BBB).6
Therefore, the identification of highly selective mTOR
inhibitors with optimized brain permeability is an ongoing
challenge for the treatment of CNS disorders. Lead
optimization strategies on different scaffolds led to the
discovery of ATP-competitive mTOR kinase inhibitors (TORKi)
a Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel,
Switzerland. E-mail: Matthias.Wymann@Unibas.ch
b Pharmaceutical Biology, Pharmacenter, University of Basel, Klingelbergstrasse 50,
4056 Basel, Switzerland
c PIQUR Therapeutics AG, Hochbergerstrasse 60, 4057 Basel, Switzerland
† Electronic supplementary information (ESI) available: Experimental procedures
and characterisation for all new compounds. Experimental details and raw data
for biological assays, 1H, 13C NMR, HRMS spectra and HPLC chromatograms for
all novel compounds. See DOI: 10.1039/d0md00408a
‡ These authors have contributed equally.
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Table 1 Heteroaromatic rings investigation
a
Cellular assays IC50 [nM]
In vitro binding assays Kib [nM]
Name
Ar
pPKB S473
94 2.5
pS6 S235/236
PI3Kα
mTOR
SIc
clog Pd
PSAd
12be
60 13
55 5.5
261 7.1
1695 277
8.0 0.92
212
1.74
102.5
1e
2
77 6.8
512 59
536 22
806 20
5.1 0.4
58 5.8
105
14
1.85
2.38
102.5
102.5
3
162 3.1
84 20
847 216
11 2.4
77
1.84
102.5
4
135 14
133 16
80 7.8
61 12
1547 278
2147 400
8.2 0.6
10 1.6
189
215
1.80
2.59
102.5
89.6
5e
6
7
157 5.4
253 10
102 4.2
67 4.8
2485 251
232 33
15 2.8
12 0.7
166
19
2.37
2.82
89.6
89.6
8
9
116 7.5
1089 34
119 9.9
776 138
17 0.30
272 10
34 9.9
0.5
2.3
2.33
3.46
102.5
89.6
118 9.6
10
446 45
549 56
694 131
348 44
55 0.93
249 39
0.22
3.11
3.46
102.5
89.6
11
>20 000
33 1.3
>600
a
b
IC50s were measured using a 7-point 1 : 2 serial dilution and each concentration was measured in triplicate. Compounds were tested for the
in vitro binding to the ATP-binding site of PI3Kα and mTOR using a commercially available LanthaScreen time-resolved FRET (TR-FRET)
displacement assay. IC50s were measured using a 10-point 1 : 4 serial dilution. Each concentration was performed in duplicate, IC50 to Ki
c
conversion factor = 9.84 (p110α), 2.05 (mTOR). Data are reported as mean
SD. Selectivity index calculated as Ki(mTOR)/Ki(p110α).
Calculation of log P and PSA was performed with ChemAxon (https://www.chemaxon.com). e Previously reported in ref. 14.
d
(S)-sulfamidate 22 using n-BuLi and copper(I) iodide (cat.)
followed by acidic hydrolysis of the intermediary sulfaminic
acid and base-mediated ring closure.14 To introduce a 1,2,4-
thiadiazole and a pyrazine, a tributyltin group was appended
on 13, followed by Stille coupling between 14 and halides
(Scheme 1a). The Stille reaction of 3-bromo-5-chloro-1,2,4-
thiadiazole was regioselective for C-5 coupling to give bromo
derivative 15. In contrast, no site-selective cross-coupling
between the tin derivative 14 and 3-chloro-6-iodopyridazine
was observed, and a mixture of chloro and iodo derivatives
was obtained (16, 50% chloro, 44% iodo; see ESI†). The
heteroaryl halide 16 was aminated by treatment with aqueous
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ammonia at 100 °C to yield the desired pyridazine-
substituted compound 3 in moderate yield. The conversion
of the bromide 15 into an amine by using ammonia was not
successful. tert-Butyl carbamate in presence of caesium
carbonate was employed for the Pd-catalysed synthesis of the
N-Boc-protected derivative of 15. In a one-pot procedure,
treatment with HCl in dioxane generated the final 1,2,4-
thiadiazole derivative 2. To prepare the 1,3,4-thiadiazole-
substituted compound 4, the chloropyrimidine 13 was
converted into the nitrile 17 using tetraethylammonium
cyanide in presence of DABCO. Coupling of nitrile 17 and
thiosemicarbazide followed by cyclization at 65 °C in
presence of TFA yielded compound
Subsequently, thiazole and difluoromethyl-
trifluoromethyl-substituted pyridines/pyrimidines
4
(Scheme 1c)
and
were
installed on intermediate 13 using a Suzuki cross-coupling
reaction with boronic acid pinacol esters to generate the final
compounds 6–11 (Schemes 1b and 2).
Scheme 2 Synthesis of compounds 7–11. Reagents and conditions: (viii)
morpholine derivative, DIPEA, DCM, 0 °C → rt, o/n; (ix) 1) n-BuLi, CuI, −78
°C → r.t., o/n; 2) HCl conc., MeOH, 45 °C, 4–6 h; 3) NaOH, H2O, r.t., 1–16
h; (x) 1) boronic ester (for 7, 9–11) or boronic ester generated in situ (for
8), XPhosPdG2 (cat.), K3PO4, dioxane/H2O, 95 °C, 2–16 h; 2) HCl,
dioxane/H2O, 60 °C, 3–16 h (for 7–9, 11). See ESI† for details.
Results and discussion
The library was tested for in vitro binding to recombinant
mTOR and PI3Kα (Ki), and for PI3K/mTOR signalling in A2058
melanoma cells (IC50 for phosphorylated S6 ribosomal protein
[pS6, Ser235/236] and phosphorylated protein kinase B [PKB/
Akt, Ser473] to detect mTORC1 and mTORC2 activity). The
in vitro and cellular profiling of the novel set of
conformationally restricted compounds is reported in Table 1.
Pyrimidine (1), pyrazine (3) and pyridine (5) have been
compared with their bioisosters involving the replacement of
–CHCH– by sulphur. Replacement of the pyrimidine with a
1,2,4-thiadiazole led to a >10-fold decrease in mTOR affinity,
reducing compound selectivity [Ki(mTOR) 1 = 5.1 nM, 2 = 58
nM; Ki(PI3Kα)/Ki(mTOR) 1 = 105, 2 = 14]. On the contrary,
comparable activity and selectivity were observed for the
bioisosteric pairs 3–4 and 5–6 (Table 1). The presence of a
difluoro or trifluoromethyl group in para-position of 2-amino
pyridines (7 and 9) caused a selectivity drop compared to 12b
[Ki(PI3Kα)/Ki(mTOR) <20]. The pyrimidine derivatives 8 and 10
were more potent on PI3Kα than on mTOR kinase [Ki(PI3Kα)/
Ki(mTOR) <1]. A gain in mTOR potency and selectivity over
PI3K was achieved moving the CF3-group from para
(compound 9) to meta position (11) on the pyridine scaffold. 11
showed the highest selectivity [Ki(PI3Kα)/Ki(mTOR) >600]
among these tricyclic derivatives, and outperformed the
selectivity of 12b. Compound 11 displayed a moderate cellular
activity (IC50 for phosphorylated PKB/Akt and for
phosphorylated S6 <550 nM).
While difluoromethyl- and trifluoromethyl-substituted
pyridines/pyrimidines have been explored in pre-clinical and
clinical candidates targeting the PI3K–mTOR pathway,10,19–21
to the best of our knowledge no mTOR inhibitor bearing
thiazole or 1,3,4-thiadiazole moieties has been disclosed yet.
With no prior hints to stability information, we characterised
compounds 4 and 6 with respect to their CYP related
metabolism, after incubation with individual human
recombinant CYP isoenzymes CYP1A1 and CYP1A2. These
isoenzymes have been selected since they are known to be
implicated in the metabolism of structurally similar
molecules.19 4 was highly stable with both CYP1A1 and 1A2
Scheme 1 Synthesis of compounds 2–4, 6. Reagents and conditions:
(a) (i) Pd(amphos)Cl2, bis(tributyltin), dioxane, reflux, 3 h; (ii) halide
derivative, Pd(PPh3)4, dioxane, 90 °C, o/n; (iii) 1) Pd2(bda)3/xantphos,
tert-butyl carbamate, Cs2CO3, dioxane, 90 °C, o/n, 2) HCl in dioxane
(for 2); (iv) NH3 aq., DMSO, 100 °C, o/n (for 3). (b) (v) 1) boronic ester,
XPhosPdG2 (cat.), K3PO4, dioxane/H2O, 95 °C, 2–16 h; 2) HCl, dioxane/
H2O, 60 °C, 3–16 h; (c) (vi) tetraethylammonium cyanide, DABCO,
DMSO, 140 °C, 1.5 h. (vii) TFA, 65 °C, o/n. See ESI† for details.
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(>70% remaining compound after 60 minutes of incubation,
Fig. 1). 6 displayed moderate to high stability with CYP1A1
and CYP1A2 (48% and 87% remaining compound,
respectively), and comparable to that of the corresponding
bioisosteric compound
5 (Fig. 1). Moreover, the (R)-3-
methylmorpholine derivative 5 presented a higher stability
with 1A1 isoenzyme with respect to the corresponding
unsubstituted-morpholine 27 (see ESI†). Due to the highly
variable expression of CYP1A1 in liver and extrahepatic
tissues, the high stability towards degradation by CYP1A1
isoenzyme is an asset in drug development and facilitates the
establishment of a therapeutic dose.
The observed SAR was rationalized using computational
modelling studies. We investigated the putative interactions
of 1–6 and 11 with ATP-binding sites of mTOR and PI3Kα.
After energy minimization, the mTOR–ligand complexes
maintained pivotal interactions including H-bonds (i)
between Asp2195 and the NH2-group of the aminopyridine,
and (ii) between the oxygen atom of the (R)-3-
methylmorpholine and the hinge region backbone amide of
Val2240. The (R)-3-methylmorpholine has been previously
reported as a crucial feature to achieve selectivity for mTOR
kinase over PI3Ks.12,14 The orientation of the amino group on
the 1,3,4-thiadiazole in 4 and on thiazole in 6 resembles that
of the 2-amino substituted pyrimidine (1), pyrazine (3) and
pyridine (5, Fig. 2b for 3–4), leading to the establishment of
an H-bond network with Asp2195 and Glu2190. On the
contrary, the NH2-group on the 1,2,4-thiadiazole (2) is 2.8 Å
away from the 2-amino group of 1. The different orientation
prevents an H-bond interaction with Glu2190 (6 Å distance),
which plays a pivotal role in the stabilization of inhibitor
binding (Fig. 2a). This explains the reduced affinity for mTOR
kinase of 2 with respect to compounds 1, 3–6. Docking
studies of compound 11 into PI3Kα and mTOR revealed that
the 3-trifluoromethyl group is well accommodated in mTOR
(Fig. 2c), while it induces steric clashes with Lys802 and
Asp933 in PI3Kα (Fig. 2d). This is due to the different
orientation of Lys2187 (mTOR) and Lys802 (PI3Kα), which
leads to a broader binding affinity pocket in mTOR compared
to that of PI3Kα. The orientation of Lys2187 (mTOR)/Lys802
Fig.
2
(a and b) Superimposition of (a) mTOR–1 and mTOR–2
complexes and (b) mTOR–3 and mTOR–4 complexes. mTOR, grey; 1,
green; 2, brown; 3, yellow; 4, cyan. The distances between the
2-amino group and Glu2190/Asp2195 are depicted as dashed black
lines. Distances values are coloured as the inhibitors. (c and d) Docking
of compound 11 (magenta) to (a) mTOR (grey) starting from PDB
4JT6,22 and (b) PI3Kα (wheat) starting from PDB 6OAC.21 No steric
clashes are present with Asp2357 and Lys2187 in mTOR (c). Steric
clashes with Asp933 and Lys802 in PI3Kα are shown (d).
(PI3Kα) is conserved among the different X-ray
crystallographic structures (Fig. S1†).
To assess the potential for BBB penetration of 4, 6 and 11,
the apparent permeability (Papp) and the efflux ratio (ER =
Papp basolateral-apical/Papp,apical-basolateral) across cell monolayers
were assessed using an in vitro TransWell assay. CRISPR-Cas9
,
generated MDCK cells expressing human MDR1, but no
endogenous canine MDR1 (MDCK-hMDR1cMDR1-ko
) were
Fig. 3 (a) Efflux ratio (ER) in MDCK cells with and without hMDR1
grown on TransWell filters. An ER of 1 is indicative of the compound
not being a hMDR1 substrate. (b) Apparent permeability (Papp) from
apical to basolateral site in MDCK-hMDR1cMDR1ko cells. Numerical
values are reported in Tables S1 and S2.† *p < 0.05, unpaired t-test,
GraphPad Prism 8.0.2.
Fig. 1 Pie chart showing the percentage of remaining compounds 4–6
and 27 (blue) after 60 min of incubation with the indicated human
recombinant CYP isoenzymes.
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employed,23 and the results compared with a control cell line
expressing neither MDR1 ortholog (MDCKcMDR1-ko).
Compounds 4 and 6, as well as 12b included as negative
control, were identified as hMDR1 substrates (ER > 20) with
low permeability (Papp < 60 × 10−6 cm s−1), predicting poor
BBB permeability in vivo. On the contrary, compound 11 was
no hMDR1 substrate (ER ∼ 1) and showed a Papp comparable
to PQR30919 and PQR620,10 which are known brain penetrant
PI3K and/or mTOR inhibitors (Fig. 3).
7 Z. Jin, H. Niu, X. Wang, L. Zhang, Q. Wang and A. Yang,
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Borsari, P. Hillmann, A. M. Sele, F. Beaufils, M. Zvelebil, P.
Hebeisen, W. Loscher, J. Burke, D. Fabbro and M. P.
Wymann, J. Med. Chem., 2018, 61, 10084–10105.
Conclusion
In summary, we have identified 3-CF3-substituted pyridine,
thiazole and 1,3,4-thiadiazole as unexplored heteroaromatic
rings for mTOR inhibitors providing an exquisite mTOR
selectivity. We have reported the first tricyclic pyrimido-
pyrrolo-oxazine derivative showing MDCK-based BBB
permeability. Altogether, the good in vitro/cellular potency,
and the predicted brain penetration qualify 11 as second-
generation tricyclic pyrimido-pyrrolo-oxazine with potential
application in the treatment of CNS disorders.
11 C. Borsari, E. Keles, D. Rageot, A. Treyer, T. Bohnacker, L.
Bissegger, M. De Pascale, A. Melone, R. Sriramaratnam, F.
Beaufils, M. Hamburger, P. Hebeisen, W. Löscher, D.
Fabbro, P. Hillmann and M. P. Wymann, J. Med. Chem.,
2020, 63(22), 13595–13617.
12 S. Bonazzi, C. P. Goold, A. Gray, N. M. Thomsen, J. Nunez,
R. G. Karki, A. Gorde, J. D. Biag, H. A. Malik, Y. Sun, G.
Liang, D. Lubicka, S. Salas, N. Labbe-Giguere, E. P. Keaney,
S. McTighe, S. Liu, L. Deng, G. Piizzi, F. Lombardo, D.
Burdette, J.-C. Dodart, C. J. Wilson, S. Peukert, D. Curtis,
L. G. Hamann and L. O. Murphy, J. Med. Chem., 2020, 63,
1068–1083.
Conflicts of interest
PH is a past employee of PIQUR Therapeutics AG, Basel; and
PH and MPW are shareholders of PIQUR Therapeutics AG.
13 V. Cmiljanovic, P. Hebeisen, E. Jackson, F. Beaufils, T.
Bohnacker and M. P. Wymann, WO2015049369, 2015.
14 C. Borsari, D. Rageot, A. Dall'Asen, T. Bohnacker, A. Melone,
A. M. Sele, E. Jackson, J.-B. Langlois, F. Beaufils, P.
Hebeisen, D. Fabbro, P. Hillmann and M. P. Wymann,
J. Med. Chem., 2019, 62, 8609–8630.
15 N. A. Meanwell, J. Med. Chem., 2011, 54, 2529–2591.
16 J. J. Danon, T. A. Reekie and M. Kassiou, Trends Chem.,
2019, 1, 612–624.
17 J. F. Rousseau, I. Chekroun, V. Ferey and J. R. Labrosse, Org.
Process Res. Dev., 2015, 19, 506–513.
18 P. Hebeisen, A. Alker and M. Buerkler, Heterocycles, 2012, 85,
65–72.
Acknowledgements
This work was supported by the Innosuisse grant 37213.1 IP-LS,
EU Horizon 2020, ITN 675392 – Phd; the Novartis Foundation
for medical-biological Research grant 14B095; the Swiss
Commission for Technology and Innovation (CTI) by PFLS-LS
grant 17241.1; the Stiftung für Krebsbekämpfung grant 341, the
Swiss National Science Foundation grant 310030_189065 to
MPW. We thank D. Rageot, F. Beaufils, J. B. Langlois, A.
Dall'Asen and E. Teillet for advice, discussions and contributions
to synthetic efforts. A. T. and M. H. thank P. Artursson's lab
(Uppsala University, Sweden) for providing the MDCK cells.
19 F. Beaufils, N. Cmiljanovic, V. Cmiljanovic, T. Bohnacker, A.
Melone, R. Marone, E. Jackson, X. Zhang, A. Sele, C. Borsari,
J. Mestan, P. Hebeisen, P. Hillmann, B. Giese, M. Zvelebil, D.
Fabbro, R. L. Williams, D. Rageot and M. P. Wymann,
J. Med. Chem., 2017, 60, 7524–7538.
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