The design and SAR of a novel series of 2-aminopyridine based LRRK2 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2017.07.072

Leucine-rich repeat kinase 2 (LRRK2) has attracted considerable interest as a therapeutic target for the treatment of Parkinson's disease. Compounds derived from a 2-aminopyridine screening hit were optimised using a LRRK2 homology model based on mixed li

Full text of DOI:10.1016/j.bmcl.2017.07.072

Accepted Manuscript
The design and SAR of a novel series of 2-aminopyridine based LRRK2 inhib-
itors
Garrick P. Smith, Lassina Badolo, Victoria Chell, I-Jen Chen, Kenneth Vielsted
Christensen, Laurent David, Justus Alfred Daechsel, Morten Hentzer, Martin
Christian Herzig, Gitte Kobberøe Mikkelsen, Stephen P. Watson, Douglas S.
Williamson
PII:
S0960-894X(17)30779-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.07.072
BMCL 25185
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 June 2017
25 July 2017
27 July 2017
Please cite this article as: Smith, G.P., Badolo, L., Chell, V., Chen, I-J., Christensen, K.V., David, L., Daechsel,
J.A., Hentzer, M., Christian Herzig, M., Mikkelsen, G.K., Watson, S.P., Williamson, D.S., The design and SAR of
a novel series of 2-aminopyridine based LRRK2 inhibitors, Bioorganic & Medicinal Chemistry Letters (2017), doi:
http://dx.doi.org/10.1016/j.bmcl.2017.07.072
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The design and SAR of a novel series of 2-aminopyridine based LRRK2 inhibitors
Garrick P. Smith,* Lassina Badolo, Victoria Chell, I-Jen Chen, Kenneth Vielsted Christensen, Laurent David, Justus Alfred Daechsel,
Morten Hentzer, Martin Christian Herzig, Gitte Kobberøe Mikkelsen, Stephen P. Watson, and Douglas S. Williamson

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
The design and SAR of a novel series of 2-aminopyridine based LRRK2 inhibitors
Garrick P. Smith*,a Lassina Badolo,a Victoria Chell,b I-Jen Chen,b Kenneth Vielsted Christensen,a Laurent David,a Justus Alfred Daechsel,a Morten Hentzer,a
Martin Christian Herzig,a Gitte Kobberøe Mikkelsen,a Stephen P. Watsona and Douglas S. Williamsonb
aH. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
bVernalis (R&D) Ltd., Granta Park, Great Abington, Cambridge, CB21 6GB, United Kingdom
ARTICLE INFO
ABSTRACT
Article history:
Received
Leucine-rich repeat kinase 2 (LRRK2) has attracted considerable interest as a therapeutic target
IRUꢀWKHꢀWUHDWPHQWꢀRIꢀ3DUNLQVRQ¶s disease. Compounds derived from a 2-aminopyridine screening
hit were optimised using a LRRK2 homology model based on mixed lineage kinase 1
(MLK1), such that a 2-aminopyridine-based lead molecule 45, with in vivo activity, was
identified.
Revised
Accepted
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
2-Aminopyridines
3DUNLQVRQ¶V
Homology model
LRRK2
Kinativ
Leucine-rich repeat kinase 2 (LRRK2) has attracted considerable
LQWHUHVWꢀDVꢀDꢀWKHUDSHXWLFꢀWDUJHWꢀIRUꢀ3DUNLQVRQ¶VꢀGLVHDVH (PD)1-5
We initiated a medicinal chemistry effort to identify novel
LRRK2 inhibitors with potential for lead optimization. The 2-
aminopyridine 3a was identified as a hit from our in-house
screening collection. 2-Aminopyridines are well known to
possess kinase inhibitory activity: for example, Crizotinib 3b is a
c-Met/ALK inhibitor approved for the treatment of non-small cell
lung carcinoma (NSCLC) in the US10.
,
since autosomal-dominant missense mutations in LRRK2 have
been associated with an increased risk of this neurological
disorder. The pathogenic LRRK2 variant G2019S has elevated
kinase activity, and so potent, selective and brain-penetrant
inhibitors of LRRK2, which reduce its kinase activity, are needed
to validate LRRK2 inhibition as a means of therapeutic
intervention for PD. Compounds such as LRRK2-IN-1 (1)6,
GNE-7915 (2a)7, PF-06447475 (2b)8 and MLi-2 (2c)9 have been
used to elucidate the biology of LRRK2 in preclinical models.
3a
3b
In order to guide the optimization of 3a, a homology model was
constructed, based on mixed lineage kinase 1 (MLK1) and
refined using known LRRK2 binders. The binding model of
compound 3a was modelled using Glide11 and shown in Figure
1A. The hinge binding scaffold of compound 3a is suggested to
be the 2-aminopyridine group, which forms two hydrogen bonds
to the backbone atoms of Glu1948 and Ala1950 in the hinge of
the ATP binding site of the LRRK2 kinase domain. The methyl
pyrazole group positions its methyl substituent close to Ala2016,
a residue important for selectivity as this position varies across
kinases. The phenyl at the 5-position of the pyridine ring extends
along the hinge region towards the solvent. Compound 3a
demonstrated good apparent permeability in the MDCK cell line,
indicating potential for central nervous system (CNS)
1
2a
2c
2b
penetration, as detailed in Table 1. This was accompanied by
high in vitro intrinsic clearance, observed in both human and rat

liver microsomes. A low molecular weight of 264, a CNS
multiparameter optimization (MPO) score12 of 5.4, and a ligand
lipophilicity effiency13 (LLE) towards LRRK2 G2019S of 3.71,
however, encouraged us to pursue 3a. The aim of the initial hit
exploration was to improve the in vitro potency and the
pharmacokinetic profile sufficiently for identifying a lead
molecule with in vivo potency. Herein, we report the SAR around
this 2-aminopyridine scaffold, where the 3-pyrazolyl and 5-tolyl
substituents of 3a are modulated.
Compound 3a and analogues were prepared according to
chemistries outlined in Schemes 1±6. Compounds where the 3-
pyrazole was replaced whilst the 5-tolyl substituent was kept
constant are shown in Scheme 1, and this approach was used for
the preparation of compounds 3a and 28±31. The tolyl group was
introduced by Suzuki coupling between 2-amino-5-
bromopyridine 4 and 4-methylphenyl boronic acid to give 5.
Subsequent bromination gave 6, which allowed the introduction
of a heteroaryl group via a second Suzuki or Stille coupling to
give 7. Compounds 36, 37 and 42 were prepared as shown in
Scheme 2. 3-Bromo-2-aminopyridine 8 could be employed to
introduce the 3-heteroaryl ring via Suzuki coupling to give 9,
followed by bromination to give 10, and then a second coupling
to give 11. Additionally, 3-heteroaryl rings could be constructed,
as shown in Schemes 3, 4, 5 and 6.
(A)
Scheme 1
b
a
5
6
4
c
(B)
7
Reagents and conditions: (a) 4-Methylphenylboronic acid, Pd(PPh3)4, 1,4-
dioxane, H2O, 100 oC, 3h, 88%; (b) N-bromosuccinimide, acetonitrile, 30
min, 64%; (c) R1B(OH)2 or R1SnBu3, Pd(Ph3P)4, Cs2CO3, 1,4-dioxane.
Scheme 2
a
b
8
9
10
c
Figure 1. (A) Binding mode of 3a (green) in LRRK2 homology model. The
hinge region of LRRK2 ATP binding site is shown in grey tube. Two
hydrogen bonds formed between 3a and LRRK2 are highlighted in broken
magenta lines. (B) Binding mode of 2a (GNE-7915, magenta) in same
LRRK2 homology model and superposed with 3a (green). Hydrogen bonds
between the hinge binding motif and LRRK2 are highlighted in broken
magenta lines.
11
Reagents and conditions: (a) R1B(OH)2 or R1B(C2O2(CH3)4), Cs2CO3,
Pd(PPh3)4, 1,4-dioxane, H2O; (b) N-bromosuccinimide, KOAc, DMF, 80 oC,
60 min; (c) R2B(OH)2, Pd(Ph3P)4,Cs2CO3, 1,4-dioxane, H2O.
Triazole derivative 16 was prepared as shown in Scheme 3. 5-
Bromo-3-aminopyridine 12 was converted to ethyl carbamate 13.
Introduction of the tolyl group using Suzuki methodology gave
14. Hydrolysis of the ethyl carbamate and subsequent conversion
of the aniline to the nitrofluoropyridine 15 allowed SNAr
Table 1. In vitro profile of 2-aminopyridine hit 3a.
LRRK2 G2019S IC50
6.7 µM
(LRRK2 G2019S calc. Ki
0.46 µM, LE 0.43)
displacement using 4-methyl-1H-(1,2,3)-triazole and subsequent
LRRK2 WT IC50
16 µM
reduction of the nitro group to obtain triazole derivative 16.
(LRRK2 WT calc. Ki
0.51 µM, LE 0.44)
Human Liver Microsomes
Rat Liver Microsomes
6 L/kg/h
17 L/kg/h
MDCK Papp
16.9 x 10 -6 cm/s
0.55
MDCK (B-A/A-B) Ratio

Reagents and conditions: (a) Br2, AcOH, r.t., 18 h; (b) R1CONHNH2,
POCl3, 100 oC, (c) N-hydroxyacetamidine, TBTU, HOBt, DMF, r.t. 12 h,
78%. , (d) R2B(OH)2, Pd(PPh3)4, K2CO3, dioxane, water, 100 oC, 18 h (e) cpd
35 only Et3SiH, TFA, 0 oC, 2 h, 50% ;(f) 5-Indolylboronic acid, Pd(PPh3)4,
Cs2CO3, dioxane, water, 100 oC, 6 h, 3%
Scheme 3
c
a,b
14
12
13
Triazole derivatives 41 and 43±45 were prepared as shown in
Scheme 6. Cycloaddition of the alkyne 25 with isopropyl azide
gave triazole 26. Coupling under Suzuki conditions with the
appropriate boronic acid gave the final product 27.
d,e
f,g
Scheme 6
16
15
b
a
25
26
27
Reagents and conditions: (a) ClCO2Et, 0oC, 30 min; (b) H2SO4, HNO3, 0oC
to r.t., 16 h; (c) 4-tolylboronic acid, Pd(PPh3)4, Cs2CO3, 1,4-dioxane±water
Reagents and conditions: (a) Isopropyl azide, CuI, t-BuOH/H2O, 16 h, 65%;
(b) R2-boronate pinacol ester, Pd(PPh3)4, Cs2CO3, ethylene glycol dimethyl
ether/H2O, 140 oC, microwave, 6 h.
o
o
(7:3), 90oC, 16 h; (d) KOH, H2O, 100 C, 6 h; (e) HBF4, NaNO2, 0 C to r.t.,
4h; (f) 4-methyl-1H-(1,2,3)-triazole, K2CO3, DMF; (g) H2, Pd/C, H2, EtOH.
Initial structural exploration of 3a by variation of R1 with a range
of substituted 5-membered nitrogen-containing heterocycles is
described in Table 2. Removal of the methyl substituent, as in 28,
or the addition of the larger ethyl (30) had modest effects on
activity. Addition of an extra methyl in the 1,5-dimethylpyrazole
29 abolished activity. The 4-(1-methylimidazole) 31 was weakly
active, whilst the 1,3-oxazole 18 and triazole 16 showed
comparable potencies to 3a. An improvement in activity was
observed with the 2-cyclopropyl-1,3,4- oxadiazole substitution,
as seen with 32.
The 2-methyloxazole derivative 18 was prepared, as shown in
Scheme 4. Introduction of an acetyl group by reaction of 6 with
(1-ethoxyvinyl)tributyltin under palladium catalysis gave 17.
This then allowed formation of the 2-methyloxazole derivative
18, using dimethylacetamide dimethyl acetal and hydroxylamine.
Scheme 4
N
NH2
N
NH2
O
N
NH2
Br
b
a
N
O
Amongst all groups tried at R1, oxadiazole 32 showed the
greatest improvement in LRRK2 inhibition, compared to starting
point 3a. To understand the reasons for this, compound 32 was
modelled in the same LRRK2 homology model as described
earlier. In Figure 2, the binding mode of 32 was predicted to be
very similar to compound 3a regarding hinge binding motif. A
difference in coplanarity between compounds 32 and 3a was
observed. 7KHꢀGLKHGUDOꢀDQJOHꢀꢁijꢂꢀEHWZHHQꢀꢃ-aminopyridine and
oxadiazole was calculated to be 2.9 degrees (Figure 3), as
opposed to 21 degrees for compound 3aꢄꢀ7KHꢀKLJKHUꢀijꢀYDOXHꢀ
required for compound 3a is to avoid steric clashes of protons
coming froPꢀWKHꢀDPLQRꢀJURXSꢀDQGꢀWKHꢀꢅ¶-position of the pyrazole.
On the contrary, a much lower ij was predicted for the oxadiazole
because one of the oxadiazole nitrogens is now able to
18
17
6
Reagents and conditions: (a) tris-n-butyl(1-ethoxyvinyl)stannane,
Pd(PPh3)2Cl2, 1,4-dioxane, 100 oC, 18 h; (b) (i) N,N-dimethylacetamide
dimethylacetal, 100 oC, 18 h; (ii) NH2OH.HCl, EtOH, 90 °C, 24 h.
1,3,4-Oxadiazole derivatives 32±35, 38±40 and 1,2,4-oxadiazole
24 were prepared as shown in Scheme 5. 2-Amino-nicotinic acid
19 was brominated to give 20. This was converted to the 1,3,4-
oxdiazole 21 using the appropriately-substituted acetyl
hydrazine, or to the 1,2,4 oxadiazole 23 using N-
hydroxyacetamidine. Subsequent Suzuki coupling of 21 or 23
with the desired aryl boronic acid afforded 1,3,4-oxadiazoles of
the general structure 22. In the case of compound 35, coupling of
5-N-methylindolylboronic acid and a final reductive step using
triethysilane was employed (step e). Suzuki coupling of 5-
indolylboronic acid yielded 1,2,4-oxadiazole 24.
intramolecularly hydrogen bond to the amino NH. The
coplanarity is further enhanced by the presence of oxygen in the
5-membered aryl ring not incurring further twist with respect to
the pyridine ring. Such coplanarity appears to be beneficial for
LRRK2, possibly because of binding site complementarity. In
addition, the cyclopropyl affords better contact with Ala2016,
which was not possible with compound 3a.
Scheme 5
d,e
21
19
22
b
a
c
f
24
20
23

Table 2. Effect of pyrazole ring R1 modifications on LRRK2
inhibition.
magenta lines. The cyclopropyl group of 32 is in close contact with Ala2016.
The dihedraOꢀ DQJOHꢀ ꢁijꢂꢀ EHWZHHQꢀ WKHꢀ ꢃ-amino and oxadiazole group is
predicted to be 2.9 degrees. The potential intramolecular hydrogen bond
between the amino and oxadiazole groups is shown as a broken black line.
The clear improvement in potency at the R1 position with the 1-
cyclopropyl-1,3,4-oxadiazole was followed up with a small
variation of the 5- position as shown in Table 3. The 5-indole
substituent 33 was moderately potent, whilst potency
improvements were observed with the N-methylmorpholine
derivative 34 and the N-methyl 5-indoline 35.
LRRK2
G2019S
IC50 / cKi
(µM)
LRRK2 WT
Compound
R1
IC50/ cKi (µM)
Table 3. Effect of tolyl R2 replacements on LRRK2 inhibition.
GNE7915
-
0.046/0.0011 0.097/0.0011
3a
16
28
6.7/0.46
9.1/0.63
16/0.51
LRRK2
LRRK2
G2019S
70% inhib @
Compound
R2
WT
IC50/ cKi
(µM)
30 PM /n.d.
IC50/ cKi (µM)
33
1.6/0.1
1.3/0.037
13/0.76
11/0.63
72%inhib @
66.7PM/1.0
18
29
24/0.72
34
35
0.39/0.027
0.71/0.048
0.49/0.012
0.97/0.023
62% inhib
@ 200
49% inhib
@200 PM/4.7
PM/5.4
30
12/0.7
57/3.3
12/0.37
Re-examination of R1 with the 5-indole group as R2 was then
undertaken, and the results are listed in Table 4. The 5-indole
equivalent (36) of compound 3a displayed similar potency,
whilst the corresponding 3-pyrazole regioisomer 37 was much
weaker. Compound 42, with a methyl on the indole nitrogen,
resulted in a modest improvement of potency compared to the
desmethyl analogue 36. The 1,2,4-oxadiazole 24 was inactive.
This is likely caused by the methyl group being incompatible
with the binding site, as a result of a possible intramolecular
hydrogen bond between R1 and the 2-amino group. The 1,3,4-
oxadiazole derivatives 38, 39 and 40 showed promising potency,
of which the 2-isopropyl-1,3,4-oxadiazole derivative 39 was the
most potent. The isopropyl substituent was the most potent on the
1,3,4-oxadiazole derivatives, and methylated indole also seems to
give an improved potency. These optimal substituents were
therefore combined in the triazole derivative 41. This compound
displayed improved potency compared to 36.
60% inhib
31
32
@200 PM/3.5
2.2/0.13
2.3/0.068
Figure 2. Binding mode of 32 (orange) in LRRK2 homology model. The
hinge region of the LRRK2 ATP binding site is shown in grey tube. Two
hydrogen bonds formed between 32 and LRRK2 are highlighted in broken

Table 4. Effect of R1 and R3 substitution on LRRK2 inhibition.
Table 5. Effect of morpholine substitution on LRRK2 inhibition.
LRRK2
Comp
R1
R3
H
G2019S
LRRK2 WT
ound
LRRK2
IC50/cKi (µM)
13/ 0.8
IC50/cKi (µM)
75% inhib
LRRK2 WT
G2019S
IC50/cKi
36
Compound
R
IC50/cKi
(µM)
@ 200 µM/ n.d.
(µM)
43
0.28/0.020
0.34/0.08
37
38
H
H
65% inhib @
40 µM/ n.d.
48% @200 µM/ n.d.
44
45
0.34/0.023
0.16/0.011
0.60/0.014
3.6/0.25
n.d.
0.30/0.007
24
39
H
H
n.a./ n.d.
n.a./ n.d.
n.d.
Encouragingly, the most potent compound 45 (LRRK2 G2019S
calc. Ki 11 nM) had an LE of 0.39, which compared favourably
with that of the start point 3a (LE 0.43, based on LRRK2
G2019S calc. Ki 460 nM). Compound 45 had an aqueous
solubility measured to be 36 µg/mL at pH 7.4; an improvement
compared to 11 µg/mL for compound 3a. Compound 45 was
profiled in more depth to ascertain its suitability for lead
optimization. The compound was assessed in the human MDCK
assay as having good permeability with no efflux liability.
Intrinsic clearance was assessed to be low in human and
moderate in rat liver microsomes (LM). These properties,
together with a high MPO score of 5.70, LLE of 5.90 and
acceptable molecular weight of 378.5, encouraged us to
investigate this compound further.
0.91/0.063
40
H
2.9/0.17
77% inhib
@22PM/0.19
41
Me
0.54/0.037
0.55/0.013
Table 6. Key in vitro parameters for 45.
LRRK2 G2019S IC50
160 nM
(LRRK2 G2019S calc. Ki
11 nM, LE 0.39)
LRRK2 WT IC50
300 nM
(LRRK2 WT calc. Ki
7 nM, LE 0.40)
42
Me
5.8/0.48
64% inhib
@ 30PM/n.d.
Human Liver Microsomes
Rat Liver Microsomes
1.2 L/kg/h
9.4 L/kg/h
26.33 x 10-6 cm/s
0.68
Based on proposed binding models of the 2-aminopyridine series
(Figures 1 and 2), it was clear that the 4 position of the R2 phenyl
points to solvent, hence a good vector to use for improving
physicochemical properties. Attempts to improve the
physicochemical properties of this series of 2-aminopyridine
based LRRK2 inhibitors by replacement of the indole with water
solubilizing groups attached to the 4 position of the R2 phenyl
group are shown in Table 5. As can be seen, little difference was
observed in LRRK2 inhibitory activity between compounds 43,
44 and 45 suggesting there was space for incorporation of
solubilizing groups in this position.
MDCK Papp
MDCK Ratio (B-A)/(A-B)
Good CNS penetration was observed in mouse brain at a dose of
10 mg/kg po, with a total b/p ratio of 1.3 (Kp u,u=0.76) and a free
brain concentration estimated to be 159 nM based on in vitro
estimation of unbound brain fraction using equilibrium dialysis
of brain homogenate and buffer. Cellular potency was estimated
by monitoring inhibition of Ser935 phosphorylation in HEK293
cells transiently expressing LRRK2 WT or LRRK2 G2019S. The
cell-based IC50¶VꢀZHUHꢀPHDVXUHGꢀWRꢀEHꢀꢃꢆꢇꢇꢀDQGꢀꢈꢃꢇꢀQ0ꢉꢀ
respectively.
Kinase selectivity of compound 45 was assessed in human
peripheral blood mononuclear cells at 1 µM using the KinativTM
screening technology.14 Good selectivity was demonstrated
against 208 kinase sites with cross reactivity only being observed
against ULK (40.8%) and MAP3K1 (83.3%). Activity against
LRRK2 was moderate, with 48.5% inhibition observed.

A study of the in vivo pharmacodynamic effect of 45 on
inhibition of LRRK2 Ser935 phosphorylation was undertaken. In
vivo dosing of 45 at 50 mg/kg sc in mice showed 76% and 79%
inhibition of Ser935 phosphorylation in brain and kidney
respectively. Mean plasma and brain free concentrations of 45
were 1451 nM and 877 nM, respectively.
[12] Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A.
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[13] Edwards, M. P.; Price, D. A. Role of Physicochemical
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Drug Safety Risks; Elsevier Inc., 2010; Vol. 45.
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Graves, L. M.; Litchfield, D. W. Chem. Biol. 2011, 18,
In summary, using a LRRK2 homology model based on MLK1,
we have undertaken optimisation of a novel class of LRRK2
inhibitors in order to identify lead(s) such as compound 45,
which are sufficiently potent and brain penetrant to have in vivo
activity and as such are useful for further exploration.
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