Discovery of CNS Penetrant CXCR2 Antagonists for the Potential Treatment of CNS Demyelinating Disorders

Article abstract of DOI:10.1021/acsmedchemlett.5b00489

Structure-activity relationship exploration of the historical biarylurea series led to the identification of novel CNS penetrant CXCR2 antagonists with nanomolar potency, favorable PK profile, and good developability potentials. More importantly, the key

Full text of DOI:10.1021/acsmedchemlett.5b00489

Letter
pubs.acs.org/acsmedchemlett
Discovery of CNS Penetrant CXCR2 Antagonists for the Potential
Treatment of CNS Demyelinating Disorders
Heng Xu,*,‡ Hongfu Lu,† Zhongmiao Xu,† Linbo Luan,† Chengyong Li,† Yan Xu,† Kelly Dong,†
Jinqiang Zhang,† Xiong Li,† Yvonne Li,† Gentao Liu,† Sophie Gong,† Yong-Gang Zhao,† Ailian Liu,†
Yueting Zhang,† Wei Zhang,† Xin Cai,† Jia-Ning Xiang,† John D. Elliott,† and Xichen Lin*,†
†Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China
‡State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical
College and Chinese Academy of Medical Sciences, 1 Xiannongtan Street, Beijing 100050, P. R. China
S
* Supporting Information
ABSTRACT: Structure−activity relationship exploration of the historical biarylurea
series led to the identification of novel CNS penetrant CXCR2 antagonists with
nanomolar potency, favorable PK profile, and good developability potentials. More
importantly, the key compound 22 showed efficacy in a cuprizone-induced
demyelination model with twice daily oral administration, thereby supporting CXCR2
to be a potential therapeutic target for the treatment of demyelinating diseases such as
multiple sclerosis.
KEYWORDS: CXCR2 antagonists, CNS penetration, diarylureas, cuprizone model, demyelination and remyelination,
demyelinating disorders, multiple sclerosis
hemokines, or chemotactic cytokines, comprise a family
oligodendrocyte progenitor cells (OPCs) in the CNS.16
Cof inducible secreted molecules of small molecular weight Recently, CXCR2 was described to influence response in
(8−10 kDa).1−3 On the basis of their disposition and number
neutrophils that mediate demyelination as well as in OPCs that
mediate myelin repair, exerting both a peripheral function to
promote demyelination and a CNS mechanism to impair
remyelination.17−20 In light of its fundamental role in
demyelination and remyelination, CXCR2 antagonists may be
suitable for therapeutic development in clinical demyelinating
disorders such as multiple sclerosis (MS), a devastating
heterogeneous inflammatory demyelinating disorder of the
CNS affecting young adults.21,22
To date, a number of small molecule CXCR2 antagonists
with distinct chemical structures have been disclosed.23−31
However, earlier reports mainly focused on their applications in
peripheral diseases and none of those were described to be
CNS penetrant. As illustrated above, the CNS penetrant
CXCR2 antagonists should, in principle, have better
pharmacological effect on MS for their robust contribution to
the CNS mechanisms that control remyelination, relative to
non-CNS penetrant compounds. To identify CNS penetrant
CXCR2 antagonists for potential MS therapeutics, we focused
our attention on a series of biarylureas that not only block the
of invariant cysteines, chemokines have been grouped into four
main classes, namely, the CXC, CC, C, and CX3C families.4
Chemokines can be released from a number of inflammatory
and structural cell types following stimulation and act through
chemokine receptors that belong to the G-protein-coupled
receptor (GPCR) superfamily.5−7 Expressed on neutrophils,
lymphocytes, dendritic cells, and many other cell types,
chemokine receptors play a role in leukocyte homing, human
immunodeficiency virus entry, angiogenesis, tumor growth and
metastasis, development, and inflammation of the central
nervous system (CNS) in addition to the mediation of
migration of leukocytes to the inflammatory sites (chemo-
taxis).8−10
CXCR2, also known as IL-8RB, is an ELR+ CXC chemokine
receptor and binds a number of CXC chemokines including
CXCL1 (GRO-α), CXCL2, CXCL3, CXCL5, CXCL7, and
CXCL8 (IL-8).11 It is well documented that CXCR2 plays an
important role in the activation and recruitment of neutrophils
to sites of inflammation, providing a biological basis of
positioning CXCR2 as an appealing drug target for several
inflammatory diseases such as arthritis, chronic obstructive
pulmonary disease (COPD), asthma, and psoriasis.12−15 In
addition to neutrophils, CXCR2 is also expressed on
Received: December 18, 2015
Accepted: February 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.5b00489
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Letter
functional binding interaction between CXCR2 and its
chemokine ligands but also display a high degree of selectivity
for CXCR2 over CXCR1.25,32,33 In addition to a urea moiety
bridging two phenyl rings, the series features a phenolic group
whose acidity appears to be an important factor to the activity.
Its well-established SAR indicated placement of a bulky
electron withdrawing sulfonamide moiety at an adjacent
position to urea improved potency as well as pharmacokinetic
properties (e.g., decrease the rate of glucuronidation).32 While
urea has been one of the most widely used structure
components in the discovery of biologically active small
molecules, the urea-containing compounds usually appear to
bear less favorable physicochemical properties that usually
result in low aqueous solubility and poor permeability,34 raising
concerns on their potential of CNS penetration as crossing
brain−blood barrier (BBB) frequently requires compounds to
have fewer hydrogen bond donors/acceptors (HBD/HBA),
lower polar surface areas (PSA), higher calculated Log P
(cLogP) values, and fewer rotatable bonds (Figure 1).35,36 In
the substituted morpholine was used to replace 4-methyl-
piperazine for maintaining comparable lipophilicity as well as
HBD, this variation, however, produced lower CNS penetrant
compounds 9 and 10. While some sulfonamide compounds 5−
8 displayed an acceptable Br/Bl through optimizing lip-
ophilicity and HBD, their absolute exposures in brain (e.g.,
brain AUC) were within the range of 83−151 h·ng/g, which
apparently needs to be further increased for better accessing the
CNS target and exerting pharmacological effects subsequently.
To this end, sulfone compounds with fewer hydrogen bonding
acceptors (HBA) were explored. For alkyl sulfones, t-butyl
sulfone 14 with highest lipophilicity displayed the best CNS
penetration property with a Br/Bl of 1.04 compared to ethyl
sulfone 11 and isopropyl sulfone 12. Interestingly, cyclic alkyl
sulfones, particularly 16 and 17, were hardly detected from
brain, largely due to their poor absorption and rapid clearance.
Similar to piperazine sulfonamides (5 and 6), alkylation of the
piperidine nitrogen (21 and 22) significantly improved the Br/
Bl. More importantly, their brain exposures were also markedly
increased (e.g., brain AUC: 358 h·ng/g for 21 compared to
29.8 h·ng/g for 20), which was not seen from above
sulfonamide compounds. With such promising CNS data,
further SAR study centered on N-containing heterocyclic
sulfones. Among pyrolidine, piperidine, and azepane sulfones,
piperidine sulfones (21 and 22) showed the most favorable
CNS penetration property (Br/Bl > 0.45). Subsequently, spiro-
compounds (27−29), structurally relevant to above N-
containing heterocyclic sulfones, were also explored. While
their blood exposures were noticeably high, these spiro-
compounds rarely crossed through into the brain (Br/Bl <
0.1). The non-CNS penetration property of these spiro-
compounds was presumably due to some transporter effects,
which need to be elucidated in the future study as no
explanation could be apparently made from the perspective of
their physicochemical properties. Additionally, a couple of
amides (30 and 31) were tested; however, they were
metabolically unstable in our in vivo CNS study. Through
systemic SAR study, sulfones with optimal HBD, HBA, and
lipophilicity were found to be the most favorable for the urea
series to incorporate reasonable brain penetration properties,
compared to sulfonamides and amides. It should be also noted
that IC50s of all compounds (Table 1) measured in a CXCR2
Tango assay were below 10 nM (e.g., pIC50 > 8), confirming
that the 3-position of urea scaffold is well tolerated with various
functionalities and could be used for optimization of other
drug-like properties such as solubility, permeability, free
fraction, etc.
Figure 1. Representative urea compounds that have entered clinical
trials.
this letter, we describe our systemic structure−activity relation-
ship (SAR) study on the biarylurea series that led to
identification of novel CNS penetrant CXCR2 antagonists
with good developability profiles, whose in vivo efficacy in a
cuprizone model supported the rationale that antagonizing
CXCR2 with small molecules could be an attractive approach
for the treatment of demyelinating diseases like MS.
To begin with exploration of CNS penetrant CXCR2
antagonists, we first investigated a urea compound 1. Its
brain-to-blood ratio (Br/Bl) of the area under the curve (AUC)
was determined to be 0.14 after a single PO dose of 1.94 mg/kg
in mice. While the ratio did not meet an internal criteria set for
CNS penetrant compounds (Br/Bl > 0.3), it showed an
acceptable starting point for further optimization. According to
the previously established SAR, the 3-position of the urea
scaffold was tolerated with moieties having various sizes and
shapes. Therefore, initial SAR efforts were focused on the
sulfonamide region with an aim of reducing the number of
hydrogen bonding donors (HBD), which was usually
considered to negatively impact CNS penetration. When the
tertiary sulfonamide 4 was tested, it displayed a similar Br/Bl to
the primary sulfonamide 1 (Br/Bl = 0.17). Methylation of 4 to
convert peripheral secondary amine to tertiary amine further
reduced one HBD, and the resulting compound 5 had a marked
increase in Br/Bl from 0.17 to 0.50 (4 vs 5). The increase of
Br/Bl was also observed for another compound 6, which only
differed from 5 in a halogen atom (e.g., Br/Bl = 0.47 for 6).
Encouraged by the CNS data of 5 and 6, we varied alkyl groups
on the piperazine nitrogen. Clearly, from methyl to ethyl to
isopropyl (compounds 6−8), their Br/Bls were continuously
increased from 0.47 to 1.87, which were correlated with their
cLogPs enhanced from 3.89 to 4.73, indicating that lipophilicity
plays an important role in CNS penetration. Additionally, when
The general synthetic procedures for urea compounds
containing sulfone moieties were described in Scheme 1.
Thiol compound 32 was prepared according to a published
procedure.37 It reacted with methylsulfonate piperidine to
generate thiol ether 33, which was then oxidized to the sulfone
34 by m-chloroperoxybenzoic acid. Hydrolysis of the
benzoxazole moiety yielded the aminophenol 35, which further
coupled with isocyanates to produce the urea 36. Terminal
piperidine amine was alkylated through a reduction amination
reaction to give the products 21 and 22.
On the basis of their good CNS penetration properties as
well as reasonable cLogP and PSA values, several representative
compounds 21−24 were conducted for pharmacokinetic study
in mice following intravenous and oral administration. As
described in Table 2, these compounds demonstrated a similar
PK profile of moderate oral bioavailability (%F: 26−41%),
B
DOI: 10.1021/acsmedchemlett.5b00489
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ACS Medicinal Chemistry Letters
Letter
Table 1. SAR of the Diarylurea Series
C
DOI: 10.1021/acsmedchemlett.5b00489
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ACS Medicinal Chemistry Letters
Letter
Table 1. continued
a
b
c
pIC50 value is the average of at least two determinations. Calculated from ChemBioDraw Ultra 14.0. Obtained from actual PO dose of 1.9 mg/
d
e
kg. Obtained from actual PO dose of 3.4 mg/kg. All others in Table 1 were performed with a IP dose of 2 mg/kg in C57 BL/6 mice. Not
applicable because the concentration at time points measured was below the limit of quantification. Not tested.
f
Scheme 1. Synthesis of Urea Compounds Containing a Urea
Moiety
respectively), indicating that there is no drug−drug interaction
concern. Neither compound was observed for glutathione
adducts and hERG binding, revealing good stability and low
concern on the cardiac safety, respectively.
a
Compound 22 was tested in a cuprizone-induced demyeli-
nation model due to its superior Fu%, evidence of brain
penetration and reasonable developability profile (Figure 2). In
a
Reagents and conditions: (a) K2CO3, DMF, rt; (b) mCPBA, DCM,
rt; (c) conc. H2SO4, dioxane, H2O, 100 °C; (d) (BOC)2O, rt; (e) aryl
isocyanate, DCM, rt; (f) TFA, rt; (g) aldehyde/ketone, NaBH3CN,
AcOH, 0 °C.
Figure 2. CNS penetrant CXCR2 antagonist 22 in a cuprizone
model.33 The corpus callosum in forebrain was selected for Black−
Gold II staining. (A) From the control group without cuprizone
feeding; (B) from the vehicle group with cuprizone feeding; (C) from
the treatment group of oral b.i.d. dosing of 30 mg/kg for 9 consecutive
days after cuprizone feeding; (D) from the treatment group of oral
b.i.d. dosing of 100 mg/kg; (E) statistics results.
Table 2. Mouse PK of CNS Penetrant CXCR2
a
38
,
Antagonists
iv, 1 mg/kg
Clb
po, 2 mg/kg
DNAUC0∼∞
compd
T1/2
Vss
Cmax
%F
21
22
23
24
2.0
2.8
2.3
1.9
15.6
16.9
30.8
15.4
2.12
3.17
2.82
1.72
132
157
125
216
299
354
212
271
30
41
41
26
this in vivo model, mice were fed with cuprizone for 5 weeks to
cause demyelinating lesions in the CNS and then orally
administrated with 22 for 9 consecutive days at doses of 30 and
100 mg/kg twice daily. When mice were sacrificed for CNS
analysis, Black−Gold myelin staining revealed severe demyeli-
nation of the corpus callosum in forebrain of the control group,
while the treatment groups showed accelerated significant
remyelination at 100 mg/kg (b.i.d., p.o.) compound 22 dosing
compared to the control vehicle group (p < 0.05).
In summary, a set of novel CNS penetrant CXCR2
antagonists were identified from the historical urea series
through systemic SAR study. To the best of our knowledge,
these urea compounds are the first CNS penetrant CXCR2
antagonists reported to date, which demonstrated nanomolar
potency (Tango assay), favorable PK profile, reasonable CNS
penetration, and good developability potential. The key
compound 22 showed efficacy in a cuprizone-induced
demyelination model through oral administration, providing
evidence to support CXCR2 to be a potential therapeutic target
to treat demyelinating diseases such as multiple sclerosis.
Future work will explore optimizing the series to help qualify
the potential therapeutic potential of CNS penetrant CXCR2
antagonists.
a
Units: T1/2, h; Clb, mL/min/kg; Vss, L/kg; Cmax, ng/mL;
DNAUC0∼∞, ng·h/mL/mg/kg.
moderate clearance (Clb: 15.4−30.8 mL/min/kg), and accept-
able oral exposure (DNAUC0∼∞: 212−354 ng·h/mL/mg/kg),
justifying further evaluation.
Some in vitro developability assays were conducted to
evaluate their drug-like properties (Table 3). The plasma free
fraction of all compounds tested here was very low,
corresponding to their high plasma protein binding. Notably,
22 had the highest human plasma free fraction, largely
attributed to its lowest lipophilicity as indicated by cLogP.
They did not show inhibitory activity in the human CYP
enzymes (pIC50 < 5 for 1A2, 2D6, 2C9, 2C19, and 3A4,
Table 3. Developability Profile of CNS Penetrant CXCR2
Antagonists
hERG
binding
(pIC50)
Fu% plasma
(human)
CYP inhibition (1A2,
2D6, 2C9, 2C19, 3A4)
GSH
conjugate
compd
21
0.1
pIC50 < 5
not
<4.1
observed
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.5b00489.
22
0.13
pIC50 < 5
not
<4
■
observed
S
23
24
0.036
0.021
pIC50 < 5
pIC50 < 5
a
<4
not
observed
a
a
Not tested.
Biological assays and experimental procedures (PDF)
D
DOI: 10.1021/acsmedchemlett.5b00489
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(20) Carlson, T.; Kroenke, M.; Rao, P.; Lane, T. E.; Segal, B. The
Th17-ELR+CXC chemokine pathway is essential for the development
of central nervous system autoimmune disease. J. Exp. Med. 2008, 205,
811−823.
AUTHOR INFORMATION
Corresponding Authors
*Phone +8610-83161089. E-mail: xuheng@imm.ac.cn.
*Phone +8621-61590718. E-mail: xichen.2.lin@gsk.com.
Notes
■
(21) Davis, F. A. Pathophysiology of multiple sclerosis and related
clinical implications. Mod. Treat 1970, 7, 890−902.
(22) Benedict, R. H.; Bobholz, J. H. Multiple sclerosis. Semin. Neurol.
2007, 27, 78−85.
The authors declare no competing financial interest.
(23) Dwyer, M. P.; Yu, Y. CXCR2 modulators: a patent review
(2009−2013). Expert Opin. Ther. Pat. 2014, 24, 519−534.
(24) Dwyer, M. P.; Yu, Y. CXCR2 Receptor Antagonists: A
Medicinal Chemistry Perspective. Curr. Top. Med. Chem. 2014, 14,
1590−1605.
(25) Widdowson, K. L.; Elliott, J. D.; Veber, D. F.; Nie, H.; Rutledge,
M. C.; McCleland, B. W.; Xiang, J.-N.; Jurewicz, A. J.; Hertzberg, R. P.;
Foley, J. J.; Griswold, D. E.; Martin, L.; Lee, J. M.; White, J. R.; Sarau,
H. M. Evaluation of potent and selective small-molecule antagonists
for the CXCR2 chemokine receptor. J. Med. Chem. 2004, 47, 1319−
1321.
(26) Dwyer, M. P.; Yu, Y.; Chao, J.; Aki, C.; Chao, J.; Biju, P.;
Girijavallabhan, V.; Rindgen, D.; Bond, R.; Mayer-Ezel, R.; Jakway, J.;
Hipkin, R. W.; Fossetta, J.; Gonsiorek, W.; Bian, H.; Fan, X.;
Terminelli, C.; Fine, J.; Lundell, D.; Merritt, J. R.; Rokosz, L. L.;
Kaiser, B.; Li, G.; Wang, W.; Stauffer, T.; Ozgur, L.; Baldwin, J.;
Taveras, A. G. Discovery of 2-Hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5-
methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobut-1-enylamino}-
benzamide (SCH 527123): A potent, orally bioavailable CXCR2/
CXCR1 receptor antagonist. J. Med. Chem. 2006, 49, 7603−7606.
(27) Porter, D. W.; Bradley, M.; Brown, Z.; Charlton, S. J.; Cox, B.;
Hunt, P.; Janus, D.; Lewis, S.; Oakley, P.; Connor, D.; Reilly, J.; Smith,
N.; Press, N. J. The discovery of potent, orally bioavailable pyrimidine-
5-carbonitrile-6-alkyl CXCR2 receptor antagonists. Bioorg. Med. Chem.
Lett. 2014, 24, 3285−3290.
(28) Maeda, D. Y.; Peck, A. M.; Schuler, A. D.; Quinn, M. T.;
Kirpotina, L. N.; Wicomb, W. N.; Fan, G.; Zebala, J. A. Discovery of 2-
[5-(4-Fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl]-
phenylboronic Acid (SX-517): Noncompetitive Boronic Acid
Antagonist of CXCR1 and CXCR2. J. Med. Chem. 2014, 57, 8378−
8397.
(29) Ha, H.; Debnath, B.; Odde, S.; Bensmn, T.; Ho, H.; Beringer, P.
M.; Neamati, N. Discovery of Novel CXCR2 Inhibitors Using Ligand-
Based Pharmacophore Models. J. Chem. Inf. Model. 2015, 55, 1720−
1738.
(30) Austin, R. P.; Bennion, C.; Bonnert, R. V.; Cheema, L.; Cook, A.
R.; Cox, R. J.; Ebden, M. R.; Gaw, A.; Grime, K.; Meghani, P.;
Nicholls, D.; Phillips, C.; Smith, N.; Steele, J.; Stonehouse, J. P.
Discovery and evaluation of a novel monocyclic series of CXCR2
antagonists. Bioorg. Med. Chem. Lett. 2015, 25, 1616−1620.
(31) Nicholls, D. J.; Wiley, K.; Dainty, I.; Maclntosh, F.; Phillips, C.;
Gaw, A.; Mardh, C. K. Pharmacological Characterization of AZD5069,
a Slowly Reversible CXC Chemokine Receptor 2 Antagonists. J.
Pharmacol. Exp. Ther. 2015, 353, 340−350.
(32) Jin, Q.; Nie, H.; McCleland, B. W.; Widdowson, K. L.; Palovich,
M. R.; Elliott, J. D.; Goodman, R. M.; Burman, M.; Sarau, H. M.;
Ward, K. W.; Nord, M.; Orr, B. M.; Gorycki, P. D.; Busch-Petersen, J.
Discovery of potent and orally bioavailable N,N′-diarylurea antagonists
for the CXCR2 chemokine receptor. Bioorg. Med. Chem. Lett. 2004, 14,
4375−4378.
ACKNOWLEDGMENTS
■
We thank Dr. Jakob Busch-Petersen for his helpful discussions.
REFERENCES
■
(1) Fernandez, E. J.; Lolis, E. Structure, function, and inhibition of
chemokines. Annu. Rev. Pharmacol. Toxicol. 2002, 42, 469−499.
(2) Laing, K. J.; Secombes, C. J. Chemokines. Dev. Comp. Immunol.
2004, 28, 443−460.
(3) Hesselgesser, J.; Horuk, R. Chemokine and chemokine receptor
expression in the central nervous system. J. NeuroVirol. 1999, 5, 13−
26.
́
(4) Murphy, P. M.; Baggiolini, M.; Charo, I. F.; Hebert, C. A.; Horuk,
R.; Matsushima, K.; Miller, L. H.; Oppenheim, J. J.; Power, C. A.
International union of pharmacology. XXII. Nomenclature for
chemokine receptors. Pharmacol. Rev. 2000, 52, 145−176.
(5) Onuffer, J. J.; Horuk, R. Chemokines, chemokine receptors and
small-molecule antagonists: recent developments. Trends Pharmacol.
Sci. 2002, 23, 459−467.
(6) Proudfoot, A. E. I. Chemokine receptors: multifaceted
therapeutic targets. Nat. Rev. Immunol. 2002, 2, 106−115.
(7) Horuk, R. Chemokine receptor antagonists: overcoming
developmental hurdles. Nat. Rev. Drug Discovery 2009, 8, 23−33.
(8) Sobolik-Delmaire, T.; Raman, D.; Sai, J.; Fan, G.; Richmond, A.
Encyclopedia of Biological Chemistry (Second Edition) 2013, 480−485.
(9) Charo, I. F.; Ransohoff, R. M. The many roles of chemokines and
chemokine receptors in inflammation. N. Engl. J. Med. 2006, 354,
610−621.
(10) Tran, P. B.; Miller, R. J. Chemokine receptors: signposts to
brain development and disease. Nat. Rev. Neurosci. 2003, 4, 444−455.
(11) Bizzarri, C.; Beccari, A. R.; Bertini, R.; Cavicchia, M. R.;
Giorgini, S.; Allegretti, M. ELR+ CXC chemokines and their receptors
(CXC chemokine receptor 1 and CXC chemokine receptor 2) as new
therapeutic targets. Pharmacol. Ther. 2006, 112, 139−149.
(12) Schwarz, M. K.; Wells, T. N. C. New therapeutics that modulate
chemokine networks. Nat. Rev. Drug Discovery 2002, 1, 347−358.
(13) Chapman, R. W.; Phillips, J. E.; Hipkin, R. W.; Curran, A. K.;
Lundell, D.; Fine, J. S. CXCR2 antagonists for the treatment of
pulmonary disease. Pharmacol. Ther. 2009, 121, 55−68.
(14) Donnelly, L. E.; Barnes, P. J. Chemokine receptor CXCR2
antagonism to prevent airway inflammation. Drugs Future 2011, 36,
465−472.
(15) Barnes, P. J. New anti-inflammatory targets for chronic
obstructive pulmonary disease. Nat. Rev. Drug Discovery 2013, 12,
543−559.
(16) Tsai, H. H.; Frost, E.; To, V.; Robinson, S.; ffrench-Constant,
C.; Geertman, R.; Ransohoff, R. M.; Miller, R. H. The chemokine
receptor CXCR2 controls positioning of oligodendrocyte precursors in
developing spinal cord by arresting their migration. Cell 2002, 110,
373−383.
(33) Busch-Petersen, J.; Wang, Y. Phenol-containing antagonists of
the CXCR2 receptor. Expert Opin. Ther. Pat. 2008, 18, 629−637.
(34) Lu, H.; Yang, T.; Xu, Z.; Wren, P. B.; Zhang, Y.; Cai, X.; Patel,
M.; Dong, K.; Zhang, Q.; Zhang, W.; Guan, X.; Xiang, J.; Elliott, J. D.;
Lin, X.; Ren, F. 2-Aminopyrimidin-4(1H)-one as the novel bioisostere
of urea: Discovery of novel and potent CXCR2 antagonists. Bioorg.
Med. Chem. Lett. 2014, 24, 5493−5496 and references therein..
(35) Hitchcock, S. A.; Pennington, L. D. Structure-brain exposure
relationships. J. Med. Chem. 2006, 49, 7559−7583.
(17) Liu, L.; Belkadi, A.; Darnall, L.; Hu, T.; Drescher, C.; Cotleur, A.
C.; Padovani-Claudio, D.; He, T.; Choi, K.; Lane, T. E.; Miller, R. H.;
Ransohoff, R. M. CXCR2-positive neutrophils are essential for
cuprizone-induced demyelination: relevance to multiple sclerosis.
Nat. Neurosci. 2010, 13, 319−326.
(18) Liu, L.; Darnall, L.; Hu, T.; Choi, K.; Lane, T. E.; Ransohoff, R.
M. Myelin Repair is accelerated by inactivating CXCR2 on
nonhematopoietic cells. J. Neurosci. 2010, 30 (27), 9074−9083.
(19) Kerstetter, A. E.; Padovani-Claudio, D. A.; Bai, L.; Miller, R. H.
Inhibition of CXCR2 signaling promotes recovery in models of
multiple sclerosis. Exp. Neurol. 2009, 220, 44−56.
(36) Mahar Doan, K. M.; Humphreys, J. E.; Webster, L. O.; Wring, S.
A.; Shampine, L. J.; Serabjit-Singh, C. J.; Adkison, K. K.; Polli, J. W.
E
DOI: 10.1021/acsmedchemlett.5b00489
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Letter
Passive permeability and P-glycoprotein-mediated efflux differentiate
central nervous system (CNS) and non-CNS marketed drugs. J.
Pharmacol. Exp. Ther. 2002, 303, 1029−1037.
(37) Palovich, M. R.; Widdowson, K. L.; Nie, H. WO 01/68033A2.
(38) All studies were conducted in accordance with the GSK Policy
on the Care, Welfare and Treatment of Laboratory Animals, and were
reviewed the Institutional Animal Care and Use Committee either at
GSK or by the ethical review process at the institution where the work
was performed.
F
DOI: 10.1021/acsmedchemlett.5b00489
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