Discovery of a pyrrolopyrimidine (JH-II-127), a highly potent, selective, and brain penetrant LRRK2 inhibitor

Article abstract of DOI:10.1021/acsmedchemlett.5b00064

Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are present in a subset of Parkinson's disease (PD) patients and may represent an attractive therapeutic target. Here we report a 2-anilino-4-methylamino-5-chloropyrrolopyrimidine, JH-II-127 (18

Full text of DOI:10.1021/acsmedchemlett.5b00064

Letter
pubs.acs.org/acsmedchemlett
Discovery of a Pyrrolopyrimidine (JH-II-127), a Highly Potent,
Selective, and Brain Penetrant LRRK2 Inhibitor
John M. Hatcher,†,‡,∥ Jinwei Zhang,§,∥ Hwan Geun Choi,†,∥ Genta Ito,§,∥ Dario R. Alessi,*,§
and Nathanael S. Gray*,†,‡
†Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States
‡Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Avenue, Longwood
Center LC-2209, Boston, Massachusetts 02115, United States
§MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland,
United Kingdom
S
* Supporting Information
ABSTRACT: Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are present in a
subset of Parkinson’s disease (PD) patients and may represent an attractive therapeutic target.
Here we report a 2-anilino-4-methylamino-5-chloropyrrolopyrimidine, JH-II-127 (18), as a
potent and selective inhibitor of both wild-type and G2019S mutant LRRK2. Compound 18
substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S
mutant at a concentration of 0.1−0.3 μM in a variety of cell types and is capable of inhibiting
Ser935 phosphorylation in mouse brain following oral delivery of doses as low as 30 mg/kg.
KEYWORDS: LRRK2, leucine-rich repeat kinase 2, Parkinson’s disease, pharmacokinetics
unusual benzamide ATP-site directed scaffold, was found to be a
potent and selective inhibitor of LRRK2.
arkinson’s disease (PD) is the second most common
Pneurodegenerative disease in the world. It affects over one
million Americans, and more than 60,000 patients are newly
diagnosed annually.1,2 Current standards of care have serious
limitations and largely address only symptoms.3 Recent genetic
studies have revealed an underlying genetic cause in at least 10%
of all PD cases,4 which provides new opportunities for the
discovery of molecularly targeted therapeutics that may
ameliorate neurodegeneration. Among the genes associated
with PD, leucine-rich repeat kinase 2 (LRRK2) is unique because
a missense mutation, G2019S, is the most frequent pathogenic
substitution found in both familial and sporadic Parkinson’s
disease cases.5,6 The G2019S mutation leads to a two- to three-
fold increase in kinase activity, which may result in activation of
neuronal death signal pathway, suggesting that small molecule
LRRK2 kinase inhibitors may be able to serve as a new class of
therapeutics for the treatment of Parkinson’s disease.7,8 Human
genetic studies conclusively implicate the G2019S mutation as
functionally relevant for Parkinson’s disease.9
However, none of these compounds are capable of effectively
inhibiting phosphorylation of Ser910 and Ser935 of LRRK2 in
mouse brain following intraperitoneal doses of up to 100 mg/kg,
which limits their use as tools in murine PD models.10,11 More
recently, we and others developed additional 2,4-diaminopyr-
imidines including HG-10-102-01 (5)14 and GNE7915 (6)15 that
are potent and selective LRRK2 inhibitors that can traverse the
blood−brain barrier. These diaminopyrimidines were shown to
significantly reduce LRRK2 activity in the brain of G2019S
LRRK2transgenic miceafteroraldosing, judgedbytheirabilityto
reduce LRRK2 phosphorylation at Ser935, a phosphorylation
that is dependent on LRRK2 catalytic activity.14,15 The
pyrrolopyrimidine PF-06447475 (7)16 was recently reported to
also be a potent and selective LRRK2 inhibitor capable of
reducing LRRK2 activity in the brain of G2019S LRRK2
transgenic mice after oral dosing. Additional ATP-competitive
LRRK2 inhibitors that have been reported include cinnolines,17
triazolopyridazines,18 and 3-cyanoquinazolines,19 as well as
several others that have appeared in the patent literature.20−24
Based on the chemical structure of GNE7915 (6), we thought
LRRK2 kinase inhibitors are being actively pursued both as
“tools” to pharmacologically interrogate normal and pathological
LRRK2biologyandasexperimental therapeutic agents (Table1).
Several 2,4-diaminopyrimidine based inhibitors of LRRK2
have been reported including LRRK2-IN-1 (1),10 CZC-25146
(2),11 and TAE684 (3).12 Additionally, GSK2578215A (4),13 an
Received: February 5, 2015
Accepted: April 7, 2015
© XXXX American Chemical Society
A
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Table 1. Comparison of Known LRRK2 Inhibitors with JH-II-127
a
IC50 (nM)
compd ID
wild-type LRRK2
13 1.8
LRRK2-G2019S
LRRK2-A2016T
LRRK2-G2019S + A2016T
LRRK2 IN 1 (1)
TAE684 (3)
6
6
9
3
0.9
0.8
1.4
0.8
2450 16
93 2.2
81 5.4
154 8.7
466 6.8
N/A
3080 10
22 2.9
61 5.5
96 2.4
382 14
N/A
8
0.5
GSK2578215A (4)
HG-10-102-01 (5)
GNE7915 (6)
11 1.9
20 3.2
1
0.5
0.3 0.2
1116
b
PF-06447475 (7)
316
6
JH II 127 (18)
0.5
2
0.3
48 3.5
20 0.9
a
GST-LRRK2(1326−2517), GST-LRRK2[G2019S](1326−2527), GST-LRRKT[A2016T](1326−2517) and GST-LRRK2[G2019S + A2016T]
b
(1326−2517) were assayed using 20 μM Nictide in the presence of 100 μM ATP. Results are average of triplicate experiments. Published results.
intramolecular hydrogen bonding was likely to exist between the
C-5 trifluoromethyl group and the NH hydrogen to give the
pseudobicycle shown in Figure 1.15 We decided to construct the
Figure 2. Molecular model of JH-II-127 with LRRK2.
Figure 1. Rationale behind the design of JH-II-127.
ring-closed version of GNE7915 (6) by designing a series of 6,5-
fused ring analogues. We reasoned that a fused bicyclic analogue
would increase thebindingaffinitydue totheadditional hydrogen
bond donor at the 7-position, which is predicted to hydrogen
bond with M1949 as shown in Figure 2. In addition, a fused
bicyclic compound should be able to better fill the hydrophobic
area around the hinge region, thus leading to an increase in
binding affinity. We have shown that a chlorine in the 5-position
of a pyrimidine interacts with the gatekeeper Met790 of EGFR to
increase the binding affinity;25 therefore, we wanted to use a
pyrrolopyrimidine, which would also allow the installation of a
chlorine at the C-5 position. We hypothesized that a chlorine at
the C-5 position would result in a more favorable interaction with
the Met1947 residue. Herein, we report our efforts to identify
bicyclic compounds with potent LRRK2 inhibition and favorable
pharmacokinetic properties.
2, compounds with a range of amine substituents exhibited
excellent potency in both the wild-type and LRRK2[G2019S]
enzymatic assays, while compounds with a methoxy group (9) or
no substituent at the C-4 position (10, 17) showed reduced
activity. Compounds 18−20 with a chlorine at the C-5 (R3)
position and amine substituents at the C-4 position also showed
excellent potency in wild-type and LRRK2[G2019S] kinase
assays.
The biochemical potency of 18 for inhibition of wild-type
LRRK2 and LRRK2[G2019S] is similar to that observed for (1);
however, 18 maintains inhibition of the A2016T mutation, which
induces dramatic resistance to LRRK2-IN-1 (1) (Figure 1).
Being mindful of other 6,5-fused bicyclic analogues, we turned
our attention toward pyrazolopyrimidines and purine analogues
(Table 3). We began by synthesizing compounds 21 and 22 with
methylamino and methoxy substitution at the C-6 (R2) position,
respectively. Interestingly, compound 22 with a methoxy
substituent at C-6 position showed greater potency in both
Webeganwiththesynthesisofpyrrolopyrimidines8−20witha
variety of substituents at the C-4 position (R2). As shown in Table
B
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Table 2. Pyrrolopyrimidine Structure−Activity Relationship (SAR) with Enzyme IC50s
Table 3. Pyrazolopyrimidine and Purine SAR with Enzyme IC50s
compd
R1
R2
R3
X
Y
Enzyme IC50 WT nM
35 0.6
Enzyme IC50 G2019S nM
44 0.2
MPO Score
21
22
23
24
H
H
H
H
NHMe
OMe
N
CH
CH
N
4.4
4.7
4.3
4.6
N
3
0.4
3
4
0.6
0.3
NHMe
OMe
H
H
CH
CH
11 0.1
19 2.1
N
18 1.6
a
wild-type and G2019S enzymatic assays than the corresponding
methylamino substituted compound 21, which was the opposite
of what was observed in the pyrrolopyrimidine series. We then
turned our attention toward pyrazolopyrimidine analogues and
made similarly substituted compounds 23 and 24. In this case, the
methylamino substituted compound was more potent than the
corresponding methoxy substituted compound.
Scheme 1. Synthesis of JH-II-127
Compound 18 was prepared from commercially available 2,4-
dichloropyrrolopyrimidine and 3-methoxy-4-nitrobenzoic acid
(Scheme 1). 3-Methoxy-4-nitrobenzoic acid 30 was subjected to
chlorination with thionyl chloride, followed by reaction with
morpholine to generate the corresponding amide 31, which was
reduced by hydrogenation to yield aniline 32. 2,4-Dichloropyrro-
lopyrimidine 25 was chlorinated using N-chlorosuccinimide
(NCS) followed by 2-(trimethylsilyl)ethoxymethyl (SEM)
protectiontogivetheSEM-protected trichloropyrrolopyrimidine
27. Compound 27 was regioselectively aminated with methyl-
amine to afford the 2,5-dichloro-N-methylpyrrolopyrimidine-4-
amine 28. Compound 28 was aminated with aniline 32 under
Buchwald coupling conditions followed by removal of the SEM
group to furnish the desired compound 18. Pyrazolopyrimidine
and purine analogues were prepared in a similar manner starting
from the corresponding dichloropyrazolopyrimidine or dichlor-
opurine.
a
Reagents and conditions: (a) NCS, THF/DCM, 90 °C, 2.5 h, 93%;
(b) NaH, SEMCl, 0 °C to RT 3 h, 90%; (c) 33% MeNH2 in EtOH,
EtOH, 70 °C 1 h, 93%; (d) 32, Pd2(dba)3, XPhos, K2CO3, sec-BuOH
90 °C, 6 h; (e) (i) TFA, DCM RT, 2 h, (ii) NaHCO3, THF, H2O, 12
h, 58%; (f) (i) toluene, thionyl chloride, 120 °C, 2 h, (ii) DIEA,
morpholine, THF, 0 °C to RT, 1 h, 92%; (g) 10% Pd/C, MeOH, RT,
12 h, 98%.
C
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A molecular docking study was then pursued based on a crystal
structure of Roco kinase (PDB accession code: 4F1T), which
revealed three hydrogen bonds to the hinge region between
backbone M1949, A1950, and the pyrrolopyrimidine. Addition-
ally, the docking study suggests the possibility of a halogen
interaction26 with M1947 and the chlorine at the 5-position of the
pyrrolopyrimidine as shown in Figure 2.
We next examined the ability of the bicyclic compounds that
showed the greatest potency in the enzymatic assay to inhibit
LRRK2 in a cellular context in comparison to LRRK2-IN-1 (1).
At the time this study was undertaken, there were no validated
direct phosphorylation substrates of LRRK2; therefore, we
monitored phosphorylation of Ser910 and Ser935, two residues
whose phosphorylation is known to be dependent upon LRRK2
kinase activity27 (Figure 3). Compound 18 was chosen as the lead
Figure 4. JH-II-127 (18) inhibits endogenously expressed LRRK2. (a)
Endogenous LRRK2 from EBV immortalized human lymphoblastoid
cellsfromacontrolsubjectandaParkinson’sdiseasepatienthomozygous
for the LRRK2[G2019S] mutation. After treatment of the cells with
DMSO or the indicated concentration of JH-II-127 (18) (or LRRK2-IN-
1 (1)) for 90min, celllysates were subjected to immunoblot analysis with
the indicated antibody for Western analysis. Immunoblots were
performed in duplicate, and results were representative of at least two
independentexperiments. (b)SameasthatinpanelaexceptmouseSwiss
3T3 cells were used. (c) Enzyme activity of JH-II-127. GST-
LRRK2(1326−2517), GST-LRRK2[G2019S](1326−2517), GST-
LRRK2[A2016T](1326−2517), and GST-LRRK2[G2019S +
A2016T](1326−2517) were assayed using 20 μM Nictide in the
presence of 100 μM ATP. Results are the average of duplicate
experiments.
Figure 3. JH-II-127 (18) inhibits LRRK2 in cells. HEK293 cells stably
expressing (a) wild-type GFP-LRRK2, (b) GFP-LRRK2[G2019S], (c)
GFP-LRRK2[G2019S+A2016T], and(d)GFP-LRRK2[A2016T] were
treated with DMSO or increasing concentrations of 18 for 90 min (1 μM
LRRK2-IN-1 was used as a control). Cell lysates were subjected to
immunoblotting for detection of LRRK2 phosphorylated at Ser910 and
Ser935 and for total LRRK2.
compound due to the combination of potency and high MPO
score.28 Compound 18 induced a dose-dependent inhibition of
Ser910 and Ser935 phosphorylation in both wild-type LRRK2
and LRRK2[G2019S] stably transfected into HEK293 cells
(Figure 3a). Substantial dephosphorylation of Ser910 and Ser935
was observed at approximately 0.3 μM concentration of 18 for
wild-type LRRK2 and LRRK2[G2019S] (Figure 3b), which is a
similar potency to that observed for LRRK2-IN-1 (1). Consistent
with the biochemical results, 18 also induced dephosphorylation
of Ser910 and Ser935 at a concentration of 0.3−1 μM in the drug-
resistant LRRK2[A2016T + G2019S] and LRRK2[A2016T]
mutants, revealing that the A2016T mutation does not induce
resistance to 18.
We next examined the effect of 18 on endogenously expressed
LRRK2inhumanlymphoblastoidcellsderivedfromacontroland
Parkinson’s patient homozygous for the LRRK2[G2019S]
mutation (Figure 4a). We found that increasing doses of 18 led
to similar dephosphorylation of endogenous LRRK2 at Ser910
and Ser935, as was observed in HEK293 cells stably expressing
wild-type LRRK2 or LRRK2[G2019S] (compare Figure 3a to
Figure 4a). Moreover, endogenous LRRK2 was also more
sensitive to 18 than LRRK2-IN-1 (1), which is consistent with
the trend we observed in HEK293 cells. We also found that 18
induced similar dose-dependent Ser935 dephosphorylation of
endogenous LRRK2 in mouse Swiss 3T3 cells (Figure 4b). IC50s
were calculated for 18 against wild-type LRRK2, G2019S,
A2016T, and G2019S + A2016T mutants, which showed that
compound 18 had an increase in potency against all of the
mutants compared to previous compounds shown in Figure 1
(Figure 4c).
The mouse pharmacokinetic profile of 18 demonstrated good
oral bioavailability (116% F), a half-life of 0.66 h, and a plasma
exposure of 3094 (h·ng/mL, AUClast) following 10 mg/kg p.o.
dosing (Table 4). Additionally, following 2 mg/kg i.v. dosing, 18
showed a plasma exposure of 533 (h·ng/mL, AUClast) and a brain
exposure of 239 (h·ng/mL, AUClast), which equates to a brain/
plasma concentration ratio of 0.45. We then compared the
pharmacodynamic properties of 18 with GNE7915 (6) by
monitoring inhibition of LRRK2 Ser910/Ser935 phosphoryla-
tion inkidney, spleen, and brainfollowingintraperitoneal delivery
of each compound at 100 mg/kg (Figure 5). We observed near
complete dephosphorylation of Ser935 of LRRK2 in all tissues
including brain at this dose for both compounds. We then
repeated the study at lower doses of 50, 30, and 10 mg/kg of 18
and 6. With 18, we observednear complete inhibition inalltissues
at 30 mg/kg but only partial inhibition in brain at the 10 mg/kg
dose. However, with 6, complete inhibition in brain was only
observed at 100 mg/kg. These results indicate that 18 is a
promising chemotype for achieving dephosphorylation of Ser935
in the brain. Interestingly, a recent study found that kinase
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Table 4. Pharmacokinetic Parameters for JH-II-127 (18)
a
b
matrix
plasma
route dose (mg/kg) Tmax (h) C0/Cmax (ng/mL) AUClast (h·ng/mL) AUGINF (h·ng/mL) T1/2 (h) CL (mL/min/kg) Vss (L/kg)
i.v.
2
1604.47
802.72
1343.6
247.35
532.67
3094.58
239.31
688.21
535.57
3867.07
246.47
762.38
0.66
62.24
1.73
p.o.
i.v.
10
2
1
1
brain
0.23
135.24
1.7
p.o.
10
a
b
C0, back extrapolated conc. for i.v. group. AUClast was considered for calculating bioavailability.
revealed that 18 significantly inhibited phosphorylation of wild-
type LRRK2 and LRRK2[G2019S] mutant at Ser910 and Ser935
at 0.3−1.0 μM in cell culture, which is approximately the same
potency as LRRK2-IN-1 (1). Compound 18 is relatively
insensitive to the A2016T mutation, which suggests that this
mutant will not be useful to validate whether the pharmacological
effects of the compound are LRRK2-dependent. Compound 18
exhibits excellent kinase selectivity as assessed by recombinant
kinases (138) and KinomeScan (451 kinases). Compound 18 can
inhibit phosphorylation of Ser935 of LRRK2 in brain and
peripheral tissues following intraperitoneal doses of 30 mg/kg.
Further optimization of this chemotype especially in regards to in
vivo half-life will be reported in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
Synthetic procedures, compound characterization, and assay
protocols. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Figure 5. Pharmacodynamic analysis for JH-II-127 (18) and GNE7915.
Pharmacodynamic study of JH-II-127 (18) and GNE7915 from brain,
spleen, and kidney following oral gavage administration at the indicated
doses. Tissues were collected, and endogenous LRRK2 was resolved by
SDS-PAGE and blotted with a phospho-specific antibody directed
against Ser935 and total LRRK2.
■
Corresponding Authors
*Phone: 1-617-582-8590. Fax: 1-617-582-8615. E-mail:
nathanael_gray@dfci.harvard.edu.
*Phone: 44-1382-385602. Fax: 44-1382-223778. E-mail: d.r.
alessi@dundee.ac.uk.
Author Contributions
inhibition reduced total LRRK2 expression causing a phenotype
similar to LRRK2 KO mice;29 however, neither of these
compounds reduced total LRRK2 expression. Additionally,
pharmacodynamic studies using our previously reported
inhibitor, HG-10-102-01, did not reveal a reduction in total
LRRK2 expression even after 6 h (see Supporting Information)
The kinase selectivity of 18 was assessed using standard
radioactivity-base enzymatic assays against a panel of 138 kinases
(Dundee profiling).30 At a concentration of 1 μM, compound 18
only inhibited the kinase activities of SmMLCK and CHK2 to
greater than 90% of the DMSO control (complete results
presented in the Supporting Information). Dose−response
analysis revealed inhibition of SmMLCK with an IC50 = 81.3
nM and CHK2 with an IC50 = 27.6 nM. KinomeScan analysis
against a near comprehensive panel of 451 kinases at a
concentration of 1 μM resulted in no interactions with kinases
other than LRRK2[G2019S] with the exception of TTK and
RPS6KA4, demonstrating the outstanding selectivity of this
inhibitor (complete profiling results provided in the Supporting
Information).31
∥These authors contributed equally to this work.
Funding
This work was supported by NIH grant P41 GM079575-03 (to
N.G.), theMedicalResearchCouncil(toD.A.), theMichaelJ. Fox
Foundation for Parkinson’s disease research (to N.G. and D.A.),
the pharmaceutical companies supporting the DSTT (AstraZe-
neca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA, and
Pfizer) (to D.A.).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We wish to thank staff at the National Centre for Protein Kinase
Profiling (www.kinase-screen.mrc.ac.uk) for undertaking Dun-
dee kinase specificity screening. SAI Advantium for performing
pharmacokinetic studies, Faycal Hentati (Institut National de
Neurologie, Tunis, Tunisia) and GlaxoSmithKline Pharmaceut-
icals R&D for providing EBV immortalized human lympho-
blastoid cells, and the antibody purification teams [Division of
Signal Transduction Therapy (DSTT), University of Dundee]
coordinated by Hilary McLauchlan and James Hastie for
generation of antibodies. Microsome stability studies were
performed by Michael Cameron (TSRI Florida).
These results suggest that 18 is a highly selective LRRK2
inhibitor; however, further profiling of additional kinases and
other ATP-dependent enzymes is still warranted.
Insummary, wehavediscovered that 18isapotentbiochemical
and cellular inhibitor of LRRK2 kinase activity. Detailed
characterization of 18 using LRRK2-IN-1 as a benchmark
E
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(16) Henderson, J. L.; Kormos, B. L.; Hayward, M. M.; Coffman, K. J.;
Jasti, J.; Kurumbail, R. G.; Wager, T. T.; Verhoest, P. R.; Noell, G. S.;
Chen, Y.; Needle, E.; Berger, Z.; Steyn, S. J.; Houle, C.; Hirst, W. D.;
Galatsis, P. Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-
7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly
potent, selective, brain penetrant, and in vivo active LRRK2 kinase
inhibitor. J. Med. Chem. 2015, 58 (1), 419−432.
ABBREVIATIONS
■
LRRK2, leucine-richrepeatkinase2;PD, Parkinson’sdisease;PK,
pharmacokinetics; F, bioavailability; AUC, area under the
concentration time curve; CL, clearance; Clast, last measured
concentration; Cmax, maximum concentration observed; T1/2
elimination half-life; Vss, volume in steady state
,
(17) Garofalo, A. W.; Adler, M.; Aubele, D. L.; Bowers, S.; Franzini, M.;
Goldbach, E.; Lorentzen, C.; Neitz, R. J.; Probst, G. D.; Quinn, K. P.;
Santiago, P.; Sham, H. L.; Tam, D.; Truong, A. P.; Ye, X. M.; Ren, Z.
Novel cinnoline-based inhibitors of LRRK2 kinase activity. Bioorg. Med.
Chem. Lett. 2013, 23 (1), 71−74.
(18) Franzini, M.; Ye, X. M.; Adler, M.; Aubele, D. L.; Garofalo, A. W.;
Gauby, S.; Goldbach, E.; Probst, G. D.; Quinn, K. P.; Santiago, P.; Sham,
H. L.; Tam, D.; Truong, A.; Ren, Z. Triazolopyridazine LRRK2 kinase
inhibitors. Bioorg. Med. Chem. Lett. 2013, 23 (7), 1967−1973.
(19)Garofalo, A.W.;Adler, M.;Aubele, D. L.;Brigham, E. F.;Chian, D.;
Franzini, M.; Goldbach, E.; Kwong, G. T.; Motter, R.; Probst, G. D.;
Quinn, K. P.; Ruslim, L.;Sham, H. L.;Tam, D.; Tanaka, P.; Truong, A. P.;
Ye, X. M.; Ren, Z. Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline
LRRK2 kinase inhibitors. Bioorg. Med. Chem. Lett. 2013, 23 (7), 1974−
1977.
(20) Galatsis, P.; Hayward, M. M.; Kormos, B. L.; Wager, T. T.; Zhang,
L.; Stepan, A. F.; Henderson, J. L.; Kurumbail, R. G.; Verhoest, P. R.
Novel 4-(substituted-amino)-7H-pyrrolo[2,3-D] Pyrimidines as LRRK2
Inhibitors. US20140005183A1, 2014.
(21) Mikkelson, G. K.; David, L.; Watson, S.; Smith, G. P.; Williamson,
D. S.; Chen, I. Aminopyridine Derived Compounds as LRRK2
Inhibitors. WO2014106612, 2014.
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DOI: 10.1021/acsmedchemlett.5b00064
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