Identification and Optimization of Benzimidazole Sulfonamides as Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists with in Vivo Activity

Journal of Medicinal Chemistry

Volumn 58, Issue 17, 2015, Pages 7057-7075

  Hennessy, Edward J ^a   Oza, Vibha ^a   Adam, Ammar ^a   Byth, Kate ^a   Castriotta, Lillian ^a   Grewal, Gurmit ^a   Hamilton, Geraldine A ^a   Kamhi, Victor M ^a   Lewis, Paula ^a   Li, Danyang ^a   Lyne, Paul ^a   Öster, Linda ^b   Rooney, Michael T ^a   Saeh, Jamal C ^a   Sha, Li ^a   Su, Qibin ^a   Wen, Shengua ^a   Xue, Yafeng ^b   Yang, Bin ^a  

^a ASTRAZENECA   (United Kingdom)

^b ASTRAZENECA R AND D   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

1 (1 ETHYL 1H BENZO[D]IMIDAZOL 2 YL)ETHANAMINE; 2 [1 (4 CHLOROPHENYLSULFONAMIDO)ETHYL] 1 ETHYL 1H BENZO[D]IMIDAZOLE 5 CARBOXAMIDE; 4 CHLORO N [1 (1 ETHYL 1H BENZO[D]IMIDAZOL 2 YL)ETHYL] BENZENESULFONAMIDE; 4 CHLORO N [1 (1 ETHYL 1H IMIDAZO[4,5 B]PYRIDIN 2 YL)ETHYL]BENZENESULFONAMIDE; 4 CHLORO N [1 (1 ETHYL 1H IMIDAZO[4,5 C]PYRIDIN 2 YL)ETHYL]BENZENESULFONAMIDE; 4 CHLORO N [1 (1 ETHYL 5 MOPHOLINO 1H BENZO[D]IMIDAZOL 2 YL)ETHYL]BENZENESULFONAMIDE; 4 CHLORO N [1 (1 ETHYL 6 METHOXY 1H BENZO[D]IMIDAZOL 2 YL)ETHYL]BENZENESULFONAMIDE; 4 CHLORO N [1 (3 ETHYL 3H IMIDAZO[4,5 B]PYRIDIN 2 YL)ETHYL]BENZENESULFONAMIDE; 4 CHLORO N [1 (3 ETHYL 3H IMIDAZO[4,5 C]PYRIDIN 2 YL)ETHYL]BENZENESULFONAMIDE; 4 CHLORO N [1 (5 CYANO 1 ETHYL 1H BENZO[D]IMIDAZOL 2 YL)ETHYL]BENZENESULFONAMIDE; 4 CHLORO N [1 (6 CHLORO 1 ETHYL 1H BENZO[D]IMIDAZOL 2 YL)ETHYL]BENZENESULFONAMIDE; 4 CHLORO N [1 (6 CHLORO 1 ETHYL 5 FLUORO 1H BENZO[D]IMIDAZOL 2 YL)ETHYL]BENZENESULFONAMIDE; 4 CHLORO N [1 [1 ETHYL 5 (HYDROXYMETHYL) 1H BENZO[D]IMIDAZOL 2 YL]ETHYL]BENZENESULFONAMIDE; 4 CHLORO N [1 [1 ETHYL 6 (HYDROXYMETHYL) 1H BENZO[D]IMIDAZOL 2 YL]ETHYL]BENZENESULFONAMIDE; 4 CHLORO N [1 [1 ETHYL 6 (TRIFLUOROMETHYL) 1H BENZO[D]IMIDAZOL 2 YL]ETHYL]BENZENESULFONAMIDE; 6 CHLORO N [1 [1 ETHYL 5 (HYDROXYMETHYL) 1H BENZO[D]IMIDAZOL 2 YL]ETHYL]BENZENESULFONAMIDE; 6 CHLORO N [1 [1 ETHYL 6 (HYDROXYMETHYL) 1H BENZO[D]IMIDAZO 2 YLL]ETHYL]BENZENESULFONAMIDE; 6 CYANO N [1 (1 ETHYL 6 METHOXY 1H IMIDAZO[4,5 C]PYRIDIN 2 YL)ETHYL]PYRIDINE 3 SULFONAMIDE; 6 CYANO N [1 (6 CYCLOPROPYL 1 ETHYL 1H IMIDAZO[4,5 C] PYRIDIN 2 YL)ETHYL]PYRIDINE 3 SULFONAMIDE; 6 CYANO N [1 [1 ETHYL 6 (TRIFLUOROMETHYL) 1H IMIDAZO [4,5 C]PYRIDIN 2 YL]ETHYL]PYRIMIDINE 3 SULFONAMIDE; ANTINEOPLASTIC AGENT; BENZIMIDAZOLE DERIVATIVE; CYTOCHROME P450 3A INDUCER; N 1 ETHYL 5 (TRIFLUOROMETHYL)BENZENE 1,2 DIAMINE; RIFAMPICIN; SPHINGOSINE 1 PHOSPHATE RECEPTOR; SULFONAMIDE; TERT BUTYL [1 [1 ETHYL 6 (TRIFLUOROMETHYL) 1H BENZO[D]IMIDAZOL 2 YL]ETHYL]CARBAMATE; TERT BUTYL [1 [[2 (ETHYLAMINO) 4 (TRIFLUOROMETHYL)PHENYL]AMINO] 1 OXOPROPAN 2 YL]CARBAMATE; UNCLASSIFIED DRUG; UNINDEXED DRUG; 6-CYANO-N-(1-(1-ETHYL-6-(TRIFLUOROMETHYL)-1H-IMIDAZO(4,5-C)PYRIDIN-2-YL)ETHYL)PYRIDINE-3-SULFONAMIDE; 6-CYANO-N-(1-(6-CYCLOPROPYL-1-ETHYL-1H-IMIDAZO(4,5-C)PYRIDIN-2-YL)ETHYL)PYRIDINE-3-SULFONAMIDE; CYTOCHROME P450 3A; PREGNANE X RECEPTOR; PYRIDINE DERIVATIVE; STEROID RECEPTOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CELL ASSAY; CONTROLLED STUDY; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG IDENTIFICATION; DRUG METABOLISM; DRUG POTENCY; DRUG SOLUBILITY; DRUG STABILITY; ENZYME INDUCTION; FEMALE; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; IN VIVO STUDY; INTERNALIZATION; LIPOPHILICITY; LIVER CELL; MAXIMUM PLASMA CONCENTRATION; MOUSE; NONHUMAN; PHARMACOPHORE; PHYSICAL PARAMETERS; PLASMA PROTEIN BINDING; RAT; REPORTER GENE; RISK REDUCTION; STRUCTURE ACTIVITY RELATION; TUMOR XENOGRAFT; ANTAGONISTS AND INHIBITORS; BIOAVAILABILITY; BIOSYNTHESIS; CELL CULTURE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG EFFECTS; DRUG SCREENING; GENETICS; METABOLISM; ORAL DRUG ADMINISTRATION; STEREOISOMERISM; SYNTHESIS;

ADMINISTRATION, ORAL; ANTINEOPLASTIC AGENTS; BENZIMIDAZOLES; BIOLOGICAL AVAILABILITY; CELLS, CULTURED; CYTOCHROME P-450 CYP3A; CYTOCHROME P-450 CYP3A INDUCERS; GENES, REPORTER; HEPATOCYTES; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PYRIDINES; RECEPTORS, LYSOSPHINGOLIPID; RECEPTORS, STEROID; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84941584876     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b01078     Document Type: Article

References (45)

1. Brinkmann, V. Sphingosine 1-phosphate receptors in health and disease: Mechanistic insights from gene deletion studies and reverse pharmacology Pharmacol. Ther. 2007, 115, 84-105 10.1016/j.pharmthera.2007.04.006
2. Adachi, K.; Kohara, T.; Nakao, N.; Arita, M.; Chiba, K.; Mishina, T.; Sasaki, S.; Fujita, T. Design, Synthesis, and Structure-Activity Relationships of 2-Substituted-2-Amino-1,3-Propanediols: Discovery of a Novel Immunosuppressant, FTY720 Bioorg. Med. Chem. Lett. 1995, 5, 853-856 10.1016/0960-894X(95)00127-F
3. Brinkmann, V.; Davis, M. D.; Heise, C. E.; Albert, R.; Cottens, S.; Hof, R.; Bruns, C.; Prieschl, E.; Baumruker, T.; Hiestand, P.; Foster, C. A.; Zollinger, M.; Lynch, K. R. The Immune Modulator FTY720 Targets Sphingosine 1-Phosphate Receptors J. Biol. Chem. 2002, 277, 21453-21457 10.1074/jbc.C200176200
4. Mandala, S.; Hajdu, R.; Bergstrom, J.; Quackenbush, E.; Xie, J.; Milligan, J.; Thornton, R.; Shei, G.-J.; Card, D.; Keohane, C.; Rosenbach, M.; Hale, J.; Lynch, C. L.; Rupprecht, K.; Parsons, W.; Rosen, H. Alteration of Lymphocyte Trafficking by Sphingosine-1-Phosphate Receptor Agonists Science 2002, 296, 346-349 10.1126/science.1070238
5. Brinkmann, V.; Billich, A.; Baumruker, T.; Heining, P.; Schmouder, R.; Francis, G.; Aradhye, S.; Burtin, P. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis Nat. Rev. Drug Discovery 2010, 9, 883-897 10.1038/nrd3248
6. Gräler, M. H.; Goetzl, E. J. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors FASEB J. 2004, 18, 551-553 10.1096/fj.03-0910fje
7. Gonzalez-Cabrera, P. J.; Hla, T.; Rosen, H. Mapping Pathways Downstream of Sphingosine 1-Phosphate Subtype 1 by Differential Chemical Perturbation and Proteomics J. Biol. Chem. 2007, 282, 7254-7264 10.1074/jbc.M610581200
8. Oo, M. L.; Thangada, S.; Wu, M.-T.; Liu, C. H.; Macdonald, T. L.; Lynch, K. R.; Lin, C.-Y.; Hla, T. Immunosuppressive and Anti-angiogenic Sphingosine 1-Phosphate Receptor-1 Agonists Induce Ubiquitinylation and Proteasomal Degradation of the Receptor J. Biol. Chem. 2007, 282, 9082-9089 10.1074/jbc.M610318200
9. Liu, Y.; Wada, R.; Yamashita, T.; Mi, Y.; Deng, C.-X.; Hobson, J. P.; Rosenfeldt, H. M.; Nava, V. E.; Chae, S.-S.; Lee, M.-J.; Liu, C. H.; Hla, T.; Spiegel, S.; Proia, R. L. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation J. Clin. Invest. 2000, 106, 951-961 10.1172/JCI10905
10. Chae, S.-S.; Paik, J.-H.; Furneaux, H.; Hla, T. Requirement for sphingosine 1-phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference J. Clin. Invest. 2004, 114, 1082-1089 10.1172/JCI200422716
11. LaMontagne, K.; Littlewood-Evans, A.; Schnell, C.; O'Reilly, T.; Wyder, L.; Sanchez, T.; Probst, B.; Butler, J.; Wood, A.; Liau, G.; Billy, E.; Theuer, A.; Hla, T.; Wood, J. Antagonism of Sphingosine-1-Phosphate Receptors by FTY720 Inhibits Angiogenesis and Tumor Vascularization Cancer Res. 2006, 66, 221-231 10.1158/0008-5472.CAN-05-2001
12. Budde, K.; Schmouder, R. L.; Brunkhorst, R.; Nashan, B.; Lücker, P. W.; Mayer, T.; Choudhury, S.; Skerjanec, A.; Kraus, G.; Neumayer, H. H. First Human Trial of FTY720, a Novel Immunomodulator, in Stable Renal Transplant Patients J. Am. Soc. Nephrol. 2002, 13, 1073-1083
13. Forrest, M.; Sun, S.-Y.; Hajdu, R.; Bergstrom, J.; Card, D.; Doherty, G.; Hale, J.; Keohane, C.; Meyers, C.; Milligan, J.; Mills, S.; Nomura, N.; Rosen, H.; Rosenbach, M.; Shei, G.-J.; Singer, I. I.; Tian, M.; West, S.; White, V.; Xie, J.; Proia, R. L.; Mandala, S. Immune Cell Regulation and Cardiovascular Effects of Sphingosine 1-Phosphate Receptor Agonists in Rodents are Mediated via Distinct Receptor Subtypes J. Pharmacol. Exp. Ther. 2004, 309, 758-768
14. 3, Respectively, Regulate Lymphocyte Recirculation and Heart Rate J. Biol. Chem. 2004, 279, 13839-13848 10.1074/jbc.M311743200
15. KACh Am. J. Transplant. 2005, 5, 529-536 10.1111/j.1600-6143.2005.00754.x
16. Gergley, P.; Nuesslein-Hildesheim, B.; Guerini, D.; Brinkmann, V.; Traebert, M.; Bruns, C.; Pan, S.; Gray, N. S.; Hinterding, K.; Cooke, N. G.; Groenewegen, A.; Vitaliti, A.; Sing, T.; Luttringer, O.; Yang, J.; Gardin, A.; Wang, N.; Crumb, W. J., Jr.; Saltzman, M.; Rosenberg, M.; Wallström, E. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate Br. J. Pharmacol. 2012, 167, 1035-1047 10.1111/j.1476-5381.2012.02061.x
17. Kunkel, G. T.; Maceyka, M.; Milstien, S.; Spiegel, S. Targeting the sphingosine-1-phosphate axis in cancer, inflammation, and beyond Nat. Rev. Drug Discovery 2013, 12, 688-702 10.1038/nrd4099
18. Davis, M. D.; Clemens, J. J.; Macdonald, T. L.; Lynch, K. R. Sphingosine 1-Phosphate Analogs as Receptor Antagonists J. Biol. Chem. 2005, 280, 9833-9841 10.1074/jbc.M412356200
19. Wei, S. H.; Rosen, H.; Matheu, M. P.; Sanna, M. G.; Wang, S.-K.; Jo, E.; Wong, C.-H.; Parker, I.; Cahalan, M. D. Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses Nat. Immunol. 2005, 6, 1228-1235 10.1038/ni1269
20. 1 antagonist in vivo Nat. Chem. Biol. 2006, 2, 434-441 10.1038/nchembio804
21. 1 Antagonist with Immunomodulatory Activities J. Immunol. 2012, 188, 206-215 10.4049/jimmunol.1101537
22. Ibrahim, M. A.; Johnson, H. W. B.; Jeong, J. W.; Lewis, G. L.; Shi, X.; Noguchi, R. T.; Williams, M.; Leahy, J. W.; Nuss, J. M.; Woolfrey, J.; Banica, M.; Bentzien, F.; Chou, Y.-C.; Gibson, A.; Heald, N.; Lamb, P.; Mattheakis, L.; Matthews, D.; Shipway, A.; Wu, X.; Zhang, W.; Zhou, S.; Shankar, G. Discovery of a Novel Class of Potent and Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists J. Med. Chem. 2012, 55, 1368-1381 10.1021/jm201533b
23. 1) Antagonist Prodrug with Efficacy in Vivo: Discovery, Synthesis, and Evaluation J. Med. Chem. 2012, 55, 9722-9734 10.1021/jm3009508
24. 1) Antagonists Bioorg. Med. Chem. Lett. 2015, 25, 2041-2045 10.1016/j.bmcl.2015.03.095
25. Oakley, R. H.; Hudson, C. C.; Cruickshank, R. D.; Meyers, D. M.; Payne, R. E., Jr.; Rhem, S. M.; Loomis, C. R. The Cellular Distribution of Fluorescently Labeled Arrestins Provides a Robust, Sensitive, and Universal Assay for Screening G Protein-Coupled Receptors Assay Drug Dev. Technol. 2002, 1, 21-30 10.1089/154065802761001275
26. Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry Nat. Rev. Drug Discovery 2007, 6, 881-890 10.1038/nrd2445
27. Lin, J. H.; Lu, A. Y. H. Inhibition and Induction of Cytochrome P450 and the Clinical Implications Clin. Pharmacokinet. 1998, 35, 361-390 10.2165/00003088-199835050-00003
28. Kocarek, T. A.; Schuetz, E. G.; Strom, S. C.; Fisher, R. A.; Guzelian, P. S. Comparative Analysis of Cytochrome P4503A Induction in Primary Cultures of Rat, Rabbit, and Human Hepatocytes Drug Metab. Dispos. 1995, 23, 415-421
29. Jones, S. A.; Moore, L. B.; Shenk, J. L.; Wisely, G. B.; Hamilton, G. A.; McKee, D. D.; Tomkinson, N. C. O.; LeCluyse, E. L.; Lambert, M. H.; Willson, T. M.; Kliewer, S. A.; Moore, J. T. The Pregnane X Receptor: A Promiscuous Xenobiotic Receptor That Has Diverged during Evolution Mol. Endocrinol. 2000, 14, 27-39 10.1210/mend.14.1.0409
30. Burk, O.; Koch, I.; Raucy, J.; Hustert, E.; Eichelbaum, M.; Brockmöller, J.; Zanger, U. M.; Wojnowski, L. The Induction of Cytochrome P450 3A5 (CYP3A5) in the Human Liver and Intestine Is Mediated by the Xenobiotic Sensors Pregnane X Receptor (PXR) and Constitutively Activated Receptor (CAR) J. Biol. Chem. 2004, 279, 38379-38385 10.1074/jbc.M404949200
31. Bertilsson, G.; Heidrich, J.; Svensson, K.; Åsman, M.; Jendeberg, L.; Sydow-Bäckman, M.; Ohlsson, R.; Postlind, H.; Blomquist, P.; Berkenstam, A. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 12208-12213 10.1073/pnas.95.21.12208
32. Lehmann, J. M.; McKee, D. D.; Watson, M. A.; Willson, T. M.; Moore, J. T.; Kliewer, S. A. The Human Orphan Nuclear Receptor PXR Is Activated by Compounds That Regulate CYP3A4 Gene Expression and Cause Drug Interactions J. Clin. Invest. 1998, 102, 1016-1023 10.1172/JCI3703
33. Kliewer, S. A.; Moore, J. T.; Wade, L.; Staudinger, J. L.; Watson, M. A.; Jones, S. A.; McKee, D. D.; Oliver, B. B.; Willson, T. M.; Zetterström, R. H.; Perlmann, T.; Lehmann, J. M. An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway Cell 1998, 92, 73-82 10.1016/S0092-8674(00)80900-9
34. Baes, M.; Gulick, T.; Choi, H.-S.; Martinoli, M. G.; Simha, D.; Moore, D. D. A New Orphan Member of the Nuclear Hormone Receptor Superfamily That Interacts with a Subset of Retinoic Acid Response Elements Mol. Cell. Biol. 1994, 14, 1544-1552
35. Raucy, J.; Warfe, L.; Yueh, M.-F.; Allen, S. W. A Cell-Based Reporter Gene Assay for Determining Induction of CYP3A4 in a High-Volume System J. Pharmacol. Exp. Ther. 2002, 303, 412-423 10.1124/jpet.102.038653
36. Lemaire, G.; de Sousa, G.; Rahmani, R. A PXR reporter gene assay in a stable cell culture system: CYP3A4 and CYB2B6 induction by pesticides Biochem. Pharmacol. 2004, 68, 2347-2358 10.1016/j.bcp.2004.07.041
37. Gao, Y.-D.; Olson, S. H.; Balkovec, J. M.; Zhu, Y.; Royo, I.; Yabut, J.; Evers, R.; Tan, E. Y.; Tang, W.; Hartley, D. P.; Mosley, R. T. Attenuating pregnane X receptor (PXR) activation: A molecular modelling approach Xenobiotica 2007, 37, 124-138 10.1080/00498250601050412
38. Salonen, L. M.; Ellermann, M.; Diederich, F. Aromatic Rings in Chemical and Biological Recognition: Energetics and Structures Angew. Chem., Int. Ed. 2011, 50, 4808-4842 10.1002/anie.201007560
39. Bjornsson, T. D.; Callaghan, J. T.; Einolf, H. J.; Fischer, V.; Gan, L.; Grimm, S.; Kao, J.; King, S. P.; Miwa, G.; Ni, L.; Kumar, G.; McLeod, J.; Obach, R. S.; Roberts, S.; Roe, A.; Shah, A.; Snikeris, F.; Sullivan, J. T.; Tweedie, D.; Vega, J. M.; Walsh, J.; Wrighton, S. A. The Conduct of in vitro and in vivo Drug-Drug Interaction Studies: A Pharmaceutical Research and Manufacturers of America (PhRMA) Perspective Drug Metab. Dispos. 2003, 31, 815-832 10.1124/dmd.31.7.815
40. Luo, G.; Cunningham, M.; Kim, S.; Burn, T.; Lin, J.; Sinz, M.; Hamilton, G.; Rizzo, C.; Jolley, S.; Gilbert, D.; Downey, A.; Mudra, D.; Graham, R.; Carroll, K.; Xie, J.; Madan, A.; Parkinson, A.; Christ, D.; Selling, B.; Lecluyse, E.; Gan, L.-S. CYP3A4 Induction by Drugs: Correlation Between a Pregnane X Receptor Reporter Gene Assay and CYP3A4 Expression in Human Hepatocytes Drug Metab. Dispos. 2002, 30, 795-804 10.1124/dmd.30.7.795
41. Lee, M.-J.; Thangada, S.; Claffey, K. P.; Ancellin, N.; Liu, C. H.; Kluk, M.; Volpi, M.; Sha'afi, R. I.; Hla, T. Vascular Endothelial Cell Adherens Junction Assembly and Morphogenesis Induced by Sphingosine-1-Phosphate Cell 1999, 99, 301-312 10.1016/S0092-8674(00)81661-X
42. Foss, F. W., Jr.; Snyder, A. H.; Davis, M. D.; Rouse, M.; Okusa, M. D.; Lynch, K. R.; Macdonald, T. L. Synthesis and biological evaluation of γ-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists Bioorg. Med. Chem. 2007, 15, 663-677 10.1016/j.bmc.2006.10.060
43. Wedge, S. R.; Kendrew, J.; Hennequin, L. F.; Valentine, P. J.; Barry, S. T.; Brave, S. R.; Smith, N. R.; James, N. H.; Dukes, M.; Curwen, J. O.; Chester, R.; Jackson, J. A.; Boffey, S. J.; Kilburn, L. L.; Barnett, S.; Richmond, G. H. P.; Wadsworth, P. F.; Walker, M.; Bigley, A. L.; Taylor, S. T.; Cooper, L.; Beck, S.; Jürgensmeier, J. M.; Ogilvie, D. J. AZD2171: A Highly Potent, Orally Bioavailable, Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor for the Treatment of Cancer Cancer Res. 2005, 65, 4389-4400 10.1158/0008-5472.CAN-04-4409
44. Smith, N. R.; James, N. H.; Oakley, I.; Wainwright, A.; Copley, C.; Kendrew, J.; Womersley, L. M.; Jürgensmeier, J. M.; Wedge, S. R.; Barry, S. T. Acute pharmacodynamic and antivascular effects of the vascular endothelial growth factor signaling inhibitor AZD2171 in Calu-6 human lung tumor xenografts Mol. Cancer Ther. 2007, 6, 2198-2208 10.1158/1535-7163.MCT-07-0142
45. Makosza, M.; Sienkiewicz, K. Hydroxylation of Nitroarenes with Alkyl Hydroperoxide Anions via Vicarious Nucleophilic Substitution of Hydrogen J. Org. Chem. 1998, 63, 4199-4208 10.1021/jo970726m