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. 2016 Feb 8;7(4):397–402. doi: 10.1021/acsmedchemlett.5b00489

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 †, Xichen Lin †,*
PMCID: PMC4834652  PMID: 27096048

Abstract

graphic file with name ml-2015-00489k_0005.jpg

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

Chemokines, or chemotactic cytokines, comprise a family of inducible secreted molecules of small molecular weight (8–10 kDa).1−3 On the basis of their disposition and number 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 (chemotaxis).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 oligodendrocyte progenitor cells (OPCs) in the CNS.16 Recently, CXCR2 was described to influence response in 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 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 this letter, we describe our systemic structure–activity relationship (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.

Figure 1.

Figure 1

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Representative urea compounds that have entered clinical trials.

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 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 lipophilicity 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.

Table 1. SAR of the Diarylurea Series.

graphic file with name ml-2015-00489k_0003.jpg

graphic file with name ml-2015-00489k_0004.jpg

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a

pIC50 value is the average of at least two determinations.

b

Calculated from ChemBioDraw Ultra 14.0.

c

Obtained from actual PO dose of 1.9 mg/kg.

d

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.

e

Not applicable because the concentration at time points measured was below the limit of quantification.

f

Not tested.

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.

Scheme 1. Synthesis of Urea Compounds Containing a Urea Moiety.

Scheme 1

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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.

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%), moderate clearance (Clb: 15.4–30.8 mL/min/kg), and acceptable oral exposure (DNAUC0∼∞: 212–354 ng·h/mL/mg/kg), justifying further evaluation.

Table 2. Mouse PK of CNS Penetrant CXCR2 Antagonistsa,38.

  iv, 1 mg/kg
 po, 2 mg/kg
compd T1/2 Clb Vss Cmax DNAUC0∼∞ %F
21 2.0 15.6 2.12 132 299 30
22 2.8 16.9 3.17 157 354 41
23 2.3 30.8 2.82 125 212 41
24 1.9 15.4 1.72 216 271 26
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a

Units: T1/2, h; Clb, mL/min/kg; Vss, L/kg; Cmax, ng/mL; DNAUC0∼∞, ng·h/mL/mg/kg.

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, 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.

Table 3. Developability Profile of CNS Penetrant CXCR2 Antagonists.

compd Fu% plasma (human) CYP inhibition (1A2, 2D6, 2C9, 2C19, 3A4) GSH conjugate hERG binding (pIC50)
21 0.1 pIC50 < 5 not observed <4.1
22 0.13 pIC50 < 5 not observed <4
23 0.036 pIC50 < 5 a <4
24 0.021 pIC50 < 5 not observed a
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a

Not tested.

Compound 22 was tested in a cuprizone-induced demyelination model due to its superior Fu%, evidence of brain penetration and reasonable developability profile (Figure 2). In 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 demyelination 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).

Figure 2.

Figure 2

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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.

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.

Acknowledgments

We thank Dr. Jakob Busch-Petersen for his helpful discussions.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.5b00489.

  • Biological assays and experimental procedures (PDF)

The authors declare no competing financial interest.

Supplementary Material

ml5b00489_si_001.pdf (1.7MB, pdf)

References

  1. Fernandez E. J.; Lolis E. Structure, function, and inhibition of chemokines. Annu. Rev. Pharmacol. Toxicol. 2002, 42, 469–499. 10.1146/annurev.pharmtox.42.091901.115838. [DOI] [PubMed] [Google Scholar]
  2. Laing K. J.; Secombes C. J. Chemokines. Dev. Comp. Immunol. 2004, 28, 443–460. 10.1016/j.dci.2003.09.006. [DOI] [PubMed] [Google Scholar]
  3. Hesselgesser J.; Horuk R. Chemokine and chemokine receptor expression in the central nervous system. J. NeuroVirol. 1999, 5, 13–26. 10.3109/13550289909029741. [DOI] [PubMed] [Google Scholar]
  4. Murphy P. M.; Baggiolini M.; Charo I. F.; Hébert 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. [PubMed] [Google Scholar]
  5. Onuffer J. J.; Horuk R. Chemokines, chemokine receptors and small-molecule antagonists: recent developments. Trends Pharmacol. Sci. 2002, 23, 459–467. 10.1016/S0165-6147(02)02064-3. [DOI] [PubMed] [Google Scholar]
  6. Proudfoot A. E. I. Chemokine receptors: multifaceted therapeutic targets. Nat. Rev. Immunol. 2002, 2, 106–115. 10.1038/nri722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Horuk R. Chemokine receptor antagonists: overcoming developmental hurdles. Nat. Rev. Drug Discovery 2009, 8, 23–33. 10.1038/nrd2734. [DOI] [PubMed] [Google Scholar]
  8. Sobolik-Delmaire T.; Raman D.; Sai J.; Fan G.; Richmond A. Encyclopedia of Biological Chemistry (Second Edition) 2013, 480–485. 10.1016/B978-0-12-378630-2.00389-3. [DOI] [Google Scholar]
  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. 10.1056/NEJMra052723. [DOI] [PubMed] [Google Scholar]
  10. Tran P. B.; Miller R. J. Chemokine receptors: signposts to brain development and disease. Nat. Rev. Neurosci. 2003, 4, 444–455. 10.1038/nrn1116. [DOI] [PubMed] [Google Scholar]
  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. 10.1016/j.pharmthera.2006.04.002. [DOI] [PubMed] [Google Scholar]
  12. Schwarz M. K.; Wells T. N. C. New therapeutics that modulate chemokine networks. Nat. Rev. Drug Discovery 2002, 1, 347–358. 10.1038/nrd795. [DOI] [PubMed] [Google Scholar]
  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. 10.1016/j.pharmthera.2008.10.005. [DOI] [PubMed] [Google Scholar]
  14. Donnelly L. E.; Barnes P. J. Chemokine receptor CXCR2 antagonism to prevent airway inflammation. Drugs Future 2011, 36, 465–472. 10.1358/dof.2011.036.06.1622072. [DOI] [Google Scholar]
  15. Barnes P. J. New anti-inflammatory targets for chronic obstructive pulmonary disease. Nat. Rev. Drug Discovery 2013, 12, 543–559. 10.1038/nrd4025. [DOI] [PubMed] [Google Scholar]
  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. 10.1016/S0092-8674(02)00838-3. [DOI] [PubMed] [Google Scholar]
  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. 10.1038/nn.2491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  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. 10.1523/JNEUROSCI.1238-10.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  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. 10.1016/j.expneurol.2009.07.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  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. 10.1084/jem.20072404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Davis F. A. Pathophysiology of multiple sclerosis and related clinical implications. Mod. Treat 1970, 7, 890–902. [PubMed] [Google Scholar]
  22. Benedict R. H.; Bobholz J. H. Multiple sclerosis. Semin. Neurol. 2007, 27, 78–85. 10.1055/s-2006-956758. [DOI] [PubMed] [Google Scholar]
  23. Dwyer M. P.; Yu Y. CXCR2 modulators: a patent review (2009–2013). Expert Opin. Ther. Pat. 2014, 24, 519–534. 10.1517/13543776.2014.887682. [DOI] [PubMed] [Google Scholar]
  24. Dwyer M. P.; Yu Y. CXCR2 Receptor Antagonists: A Medicinal Chemistry Perspective. Curr. Top. Med. Chem. 2014, 14, 1590–1605. 10.2174/1568026614666140827144615. [DOI] [PubMed] [Google Scholar]
  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. 10.1021/jm034248l. [DOI] [PubMed] [Google Scholar]
  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. 10.1021/jm0609622. [DOI] [PubMed] [Google Scholar]
  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. 10.1016/j.bmcl.2014.06.011. [DOI] [PubMed] [Google Scholar]
  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. 10.1021/jm500827t. [DOI] [PMC free article] [PubMed] [Google Scholar]
  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. 10.1021/acs.jcim.5b00181. [DOI] [PubMed] [Google Scholar]
  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. 10.1016/j.bmcl.2015.01.067. [DOI] [PubMed] [Google Scholar]
  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. 10.1124/jpet.114.221358. [DOI] [PubMed] [Google Scholar]
  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. 10.1016/j.bmcl.2004.06.097. [DOI] [PubMed] [Google Scholar]
  33. Busch-Petersen J.; Wang Y. Phenol-containing antagonists of the CXCR2 receptor. Expert Opin. Ther. Pat. 2008, 18, 629–637. 10.1517/13543776.18.6.629. [DOI] [Google Scholar]
  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. 10.1016/j.bmcl.2014.10.003. [DOI] [PubMed] [Google Scholar]
  35. Hitchcock S. A.; Pennington L. D. Structure-brain exposure relationships. J. Med. Chem. 2006, 49, 7559–7583. 10.1021/jm060642i. [DOI] [PubMed] [Google Scholar]
  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. 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. 10.1124/jpet.102.039255. [DOI] [PubMed] [Google Scholar]
  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.

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Supplementary Materials

ml5b00489_si_001.pdf (1.7MB, pdf)

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