A Potent and Selective Janus Kinase Inhibitor with a Chiral 3D-Shaped Triquinazine Ring System from Chemical Space

Article abstract of DOI:10.1002/anie.202012049

The generated databases (GDBs) enumerate billions of possible molecules following simple rules of chemical stability and synthetic feasibility. Exploring the GDBs shows that many chiral, 3D-shaped ring systems, often containing quaternary centers, have never been exploited for drug design. Shown herein is that such ring systems can be useful for medicinal chemistry by using the example of the enantioselective synthesis of triquinazine, a novel chiral piperazine analogue derived from angular triquinane. It is used to design a nanomolar and selective inhibitor of Janus Kinase 1 and is related to the marketed drug Tofacitinib, which is useful for treating autoimmune diseases.

Full text of DOI:10.1002/anie.202012049

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Accepted Article
Title: A Potent and Selective Janus Kinase Inhibitor with a Chiral 3D-
Shaped Triquinazine Ring System from Chemical Space
Authors: Kris Meier, Josep Arús-Pous, and Jean-Louis Reymond
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202012049
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A Potent and Selective Janus Kinase Inhibitor with a Chiral 3D-
Shaped Triquinazine Ring System from Chemical Space
Kris Meier,[a] Josep Arús-Pous[a] and Jean-Louis Reymond*[a]
Abstract: The Generated DataBases (GDBs) enumerate billions of
possible molecules following simple rules of chemical stability and
synthetic feasibility. Exploring the GDBs shows that many chiral, 3D-
shaped ring systems, often containing quaternary centers, have never
been exploited for drug design. Herein we show that such ring
systems can be useful for medicinal chemistry at the example of the
enantioselective synthesis of triquinazine, a novel chiral piperazine
analog derived from angular triquinane, and its use to design a
nanomolar and selective inhibitor of Janus Kinase 1 related to the
marketed drug Tofacitinib useful to treat auto-immune diseases.
S1),[29][30][31] stood out as the only chiral ring system with a
quaternary center. The other three ring systems, known both as
hydrocarbons and as nitrogen containing analogs 2,[32] 3,[33] and
4,[34] were achiral. We selected the angular diaza-triquinane 8,
here named triquinazine, as our target building block representing
a new functionalizable piperazine analog (Figure 1b).[35,36]
Innovation at the level of chemical structures is essential for drug
design and the progress of modern medicine.[1,2] The
computational exploration of chemical space has shown that the
number of possible drug-like organic molecules is extremely large
and exceeds the number of known molecules by many orders of
magnitude.[3,4] While many new molecules can be obtained by
combining known building blocks through known reactions,[5–7]
one can access a deeper level of novelty by exploring chemical
space from first principles, for example in the Generated
DataBases GDB11,[8,9] GDB13[10] and GDB17,[11,12] which
enumerate all possible molecules up to 11, 13 and 17 non-
hydrogen atoms following simple rules of chemical stability and
synthetic feasibility,[13] or their fragment-like and drug-like
subsets.[14–16] Compared to most drugs, GDB molecules have on
average a higher fraction of sp3-carbon atoms and are often
constructed on chiral 3D-shaped ring systems such as tris-
homocubane[17] and trinorbornane[18,19] (Figure 1a, ring systems
are the cyclic parts of molecules considering or not heteroatoms
and unsaturations).[20–22] Such 3D-shaped molecules have been
recently recognized as generally desirable in drug design
because they often display more favourable properties in terms of
selectivity, solubility and metabolism than “flat” molecules.[23–27]
To identify an interesting chiral 3D-shaped ring system for
drug design, we analyzed the database GDB4c containing
916,130 possible ring systems up to four rings.[28] We focused on
aliphatic five-membered rings because they might form compact
yet easily accessible 3D-shaped ring systems. Excluding spiro
centers, which are well explored, as well as ring systems
containing norbornane subunits due to their complexity, left only
20 ring systems, just four of which were tricyclic (Figure 1a).
Among these, angular triquinane 1, known as hydrocarbon and
as substructure of more complex natural products (Figure
Figure 1. a) Rings systems examples and statistics. b) Synthesis and X-ray
structure of triquinazine rac-8 (CCDC 2011191). Conditions: a) allyl acetate,
Pd(PPh3)4, DBU, THF, 22 °C, 18 h (67%); b) O3, DCM, MeOH, -78 °C then
NaBH(OAc)3, benzylamine, 20 °C, 16 h (25%); c) Pd/C, H2, HCl, MeOH, 22 °C,
5 d (20%). c) Structure of 9 and 10 and docking pose of (R)-9 (yellow) in the
active pocket of JAK3 (PDB: 3LXK) with co-crystallized Tofacitinib (grey).
[a]
Dr. Kris Meier, Dr. Josep Arús-Pous, Prof. Dr. J.-L. Reymond
Department of Chemistry and Biochemistry
University of Bern
Freiestrasse 3, 3012 Bern, Switzerland
E-mail: jean-louis.reymond@dcb.unibe.ch
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202012049
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We obtained a first sample of triquinazine 8 as a racemate starting
from cyclopentane-1,3-dione 5. Double Pd-catalyzed allylation
with allyl acetate formed the quaternary center in 6.[37] Double
ozonolysis of the pair of terminal double bonds followed by
reductive amination[38] with benzylamine then provided rac-7,
which was debenzylated to yield rac-8 as hydrochloride salt,
whose cis-fused pyrrolidine rings were confirmed by X-ray
crystallography (Figure 1b).
arthritis, and Delgocitinib was recently approved in Japan to treat
atopic dermatitis.[45,46] Docking studies using Autodock Vina[47]
and the crystal structure of JAK3 co-crystalized with Tofacitinib[48]
indicated that both enantiomers of rac-9 could adopt docking
poses comparable to the crystalized Tofacitinib (Figure 1c).
Furthermore, Janus kinases were among the highest-ranking
targets predicted for 9 or 10 using the online Polypharmacology
Browser PPB2.[49]
We synthesized our target inhibitors 9 and 10 by a modified
synthesis enabling orthogonally protected amino groups (Figure
2b). Reductive Knoevenagel condensation[50] of 5 with N-Boc-
aminoacetaldehyde in the presence of Hantzsch ester as
reducing agent first provided the monoalkylated intermediate 11.
Pd-catalyzed allylation then gave the dialkylated cyclopentane-
1,3-dione 12, which existed in a Claisen/retro-Claisen equilibrium
with the O-alkylated form. Nevertheless, Boc deprotection of 12
followed by intramolecular reductive amination and Boc
reprotection afforded cyclopentanone rac-13 in good yields.
Ozonolysis and reductive amination with benzylamine then gave
rac-14 as orthogonally protected intermediate. Debenzylation of
the first amino group and nucleophilic aromatic substitution with
6-chloro-7-deazapurine, followed by Boc deprotection of the
second amino group and acylation with either cyanoacetic acids
or acrylic acid, finally afforded rac-9 and rac-10.
In a biochemical kinase inhibition assay, rac-9 strongly
inhibited JAK1 kinase (IC50 = 1.0 nM) with 10 – 30-fold selectivity
over JAK2, JAK3 and TYK2, thus being both more potent and
more JAK1-selective than the reference drugs Delgocitinib and
Tofacitinib (Table 1). Kinome profiling showed that rac-9 only
inhibited four out of 140 human kinases above 50% at 1 µM
(Figure S3, NUAK1: 53%; SIK2: 54%, MST2: 50%; MAP4K3:
57%), confirming its’ excellent JAK1-selectivity. Note that kinase
off-targets also occur for both Delgocitinib (ROCK2: IC50 = 0.14
µM)[46] and Tofacitinib (LCK: IC50 = 0.44 µM).[46] Compared to rac-
9, rac-10 was approximately 10-fold less potent and showed a 3-
fold selectivity for JAK3 (IC50 = 9 nM) over the other three JAK
kinases, which probably reflects covalent reactivity with a cysteine
residue occurring only in the JAK3 active site, an effect also
responsible for the JAK3-kinase selectivity of PF-06651600.[42]
Table 1: JAK kinase inhibition profiles.
IC50 (nM)
JAK1
2.8
JAK2
2.6
JAK3
13
TYK2
58
Figure 2: a) Structure of JAK inhibitors. b) Synthesis of triquinazine-based JAK
kinase inhibitors. Conditions: a) BocNHCH2CHO, Hantzsch ester, L-proline,
CH2Cl2, 22 °C, 24 h, (88%); b) allyl acetate, Pd(PPh3)4, THF, 22 °C, 4.5 h; c)
TFA, CH2Cl2, 22 °C, 12 h; d) NaBH3CN, MeOH, 22 °C, 24 h; e) Boc2O, NEt3,
CH2Cl2, 22 °C, 16 h, (46% over four steps); f) O3, CH2Cl2, MeOH, -78 °C, then
DMS, 22 °C, 8 h, ; g) benzylamine, MeOH, NaBH3CN, AcOH, 22 °C, 16.5 h,
(70% over two steps); h) Pd/C, H2, AcOH, MeOH, 22 °C, 3 d; j) 6-chloro-7-
deazapurine, NEt3, NMP, 110 °C, 12 h (67% over two steps); k) HCl in MeOH,
22 °C, 18 h; ml) cyanoacetic acid, DIC, DIPEA, DMAP, CH2Cl2, 22 °C, 20 h
(52% over two steps for rac-9); n) TFA, CH2Cl2, 22 °C, 2 h; o) acrylic acid, DMAP,
EDC, DIPEA, CH2Cl2, 22 °C, 20 h, (31% oer two steps for rac-10)
Delgocitinib[46]
Tofacitinib[46]
PF-06651600[42]
rac-9a)
2.9
1.2
1.1
42
>10,000
1.0
>10,000
13
33 nM
29
>10,000
26
rac-10a)
30
53
9
183
(R)-9a)
0.8
5.4
14
52
(S)-9 b)
>1,000
>1,000
>1,000
>1,000
To obtain a drug-type molecule, we envisioned to functionalize
the secondary amino groups in rac-8 with a 7-deazapurine, a well-
known kinase hinge binder,[39] and a cyanoacetyl or acryl group to
form 9 or 10 as analogs of Delgocitinib, Tofacitinib or PF-
06651600 (Figure 1c/2a).[40–42] These drugs were developed as
inhibitors of Janus kinases JAK1/2/3 and TYK2, a family of
kinases controlling cytokine signalling.[43,44] Tofacitinib is a 2012
FDA approved blockbuster drug for the treatment of rheumatoid
a) IC50 were measured in duplicates in the presence of ATP [Km] and Ulight-
CAGAGAIETDKEYYTVKD [100nM]. b) Less than 50% inhibition at 1 µM
inhibitor concentration. All the experiments were conducted by Eurofins Cerep
SA, France.
Separating rac-9 into its enantiomers by preparative chiral-phase
HPLC revealed that only one of them was inhibitory, which was
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14 h (quant. yield over two steps); n) Pd/C, H2, AcOH, MeOH, 22 °C, 3 d; o) 6-
chloro-7-deazapurine, NEt3, NMP, 110 °C, 12 h (67% over two steps); p) HCl in
MeOH, 22 °C, 18 h; q) cyanoacetic acid, DIC, DIPEA, DMAP, CH2Cl2, 22 °C, 20
h (52% over two steps).
somewhat surprising since both enantiomers had comparably
favorable docking scores (Table 1). To identify the active
enantiomer, we developed an enantioselective synthesis (Figure
3). Reductive Knoevenagel condensation of diketone 5 with N-
benzyl-N-Boc-aminoacetaldehyde gave enol 16, which
underwent Pd-catalyzed allylation to yield the prochiral diketone
17. In contrast to 12, there was no detectable Claisen/retro-
Claisen equilibrium of diketone 17, which we reduced using
isopropanol and Noyori’s transfer hydrogenation catalyst [(S,S)-
TsDPEN]RuCl(p-cymene) to yield β-keto-alcohol (2R,3S)-18 in
excellent yields and enantioselectivity.[51,52] Boc deprotection
followed by intramolecular reductive amination then yielded
(1R,5S,8S)-19, whose absolute configuration was determined by
X-ray crystallography. Oxidizing the chiral cyclopentanol back to
the ketone and exchanging the protecting group on the secondary
amine then yielded cyclopentanone (1S,5S)-20, which was
converted to the orthogonally protected triquinazine (1R,5S,8S)-
21 by ozonolysis and intramolecular reductive amination with
benzylamine. Protecting group exchange then yielded (1R,5S,
8S)-14, which was converted to intermediate (R)-15 and finally
the single enantiomer JAK kinase inhibitor (R)-9. The same
In summary, the potent inhibition of JAK kinases observed with
(R)-9 together with an efficient enantioselective synthesis
demonstrate that our new triquinazine building block 8 can be
useful for medicinal chemistry. Note that (R)-9 did not undergo
any significant degradation over 60 min in a human liver
microsome stability assay, indicating favorable pharmacokinetic
properties for this building block (Figures S4).
In previous exploration of GDB databases we used docking
scores to select molecules and chose the synthetically most
simple cases exploiting known scaffolds for experimental
evaluation to ensure rapid access to tens of test compounds,
which allowed us to discover inhibitors with micromolar
activities.[53–57] Here we selected triquinazine for its originality and
interesting chirality, only considering docking as a hint for a
possible application. This approach required to address a
challenging synthesis producing only a few test molecules but
was rewarded by a nanomolar activity and a novel 3D-shaped
chiral tricyclic diamine scaffold with potentially broader
applicability for drug design. Apart from spiro-compounds such as
the ring system used in PF-06651600 (Figure 2a), triquinazine 8
represents one of the simplest possible 3D-shaped chiral ring
systems. Many additional variations along this theme can be
extracted from GDB4c to further enrich the repertoire of
interesting building blocks for medicinal chemistry.
synthesis
using
the
enantiomeric
catalyst
[(R,R)-
TsDPEN]RuCl(p-cymene) yielded the inactive enantiomer (S)-9
(Figure S2).
Acknowledgements
This work was supported financially by the Swiss National
Science Foundation (Grants no. 200020_178998).
Keywords: chemical space • ring systems • kinases • drug design • inhibitors
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Entry for the Table of Contents
COMMUNICATION
Exploring the chemical space
Kris Meier, Josep Arús-Pous and
database GDB4c for novel chiral ring
systems led to the design and
synthesis of triquinazine and a
functionalized analog showing
nanomolar inhibition of Janus Kinases
Jean-Louis Reymond* Page No. – Page
No.
A Potent and Selective Janus Kinase
Inhibitor with a Chiral 3D-Shaped
Triquinazine Ring System from
Chemical Space
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