Synthesis, Structure–Activity Relationship Studies, and ADMET Properties of 3‐Aminocyclohex‐2‐en‐1‐ones as Chemokine Receptor 2 (CXCR2) Antagonists
dc.contributor.author | Dai, Weiyang | |
dc.contributor.author | Chen, Wenmin | |
dc.contributor.author | Debnath, Bikash | |
dc.contributor.author | Wu, Yong | |
dc.contributor.author | Neamati, Nouri | |
dc.date.accessioned | 2018-05-15T20:14:01Z | |
dc.date.available | 2019-07-01T14:52:17Z | en |
dc.date.issued | 2018-05-08 | |
dc.identifier.citation | Dai, Weiyang; Chen, Wenmin; Debnath, Bikash; Wu, Yong; Neamati, Nouri (2018). "Synthesis, Structure–Activity Relationship Studies, and ADMET Properties of 3‐Aminocyclohex‐2‐en‐1‐ones as Chemokine Receptor 2 (CXCR2) Antagonists." ChemMedChem 13(9): 916-930. | |
dc.identifier.issn | 1860-7179 | |
dc.identifier.issn | 1860-7187 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/143675 | |
dc.description.abstract | Herein we describe the synthesis and structure–activity relationships of 3‐aminocyclohex‐2‐en‐1‐one derivatives as novel chemokine receptor 2 (CXCR2) antagonists. Thirteen out of 44 derivatives were found to inhibit CXCR2 downstream signaling in a Tango assay specific for CXCR2, with IC50 values less than 10 μm. In silico ADMET prediction suggests that all active compounds possess drug‐like properties. None of these compounds show significant cytotoxicity, suggesting their potential application in inflammatory mediated diseases. A structure–activity relationship (SAR) map has been generated to gain better understanding of their binding mechanism to guide further optimization of these new CXCR2 antagonists.Combating inflammatory disease: New derivatives of 3‐aminocyclohex‐2‐en‐1‐ones were synthesized and evaluated for their CXCR2 inhibition. Structure– activity relationship studies of these compounds were performed. Several compounds display CXCR2 IC50 values less than 10 μm, and also show selectivity against CXCR2 and low cytotoxicity. In silico ADMET prediction suggests most active compounds possess good drug‐like properties. | |
dc.publisher | Wiley Periodicals, Inc. | |
dc.subject.other | CXCR2 antagonists | |
dc.subject.other | structure–activity relationships | |
dc.subject.other | chemokine receptors | |
dc.subject.other | ADMET | |
dc.title | Synthesis, Structure–Activity Relationship Studies, and ADMET Properties of 3‐Aminocyclohex‐2‐en‐1‐ones as Chemokine Receptor 2 (CXCR2) Antagonists | |
dc.type | Article | en_US |
dc.rights.robots | IndexNoFollow | |
dc.subject.hlbsecondlevel | Natural Resources and Environmen | |
dc.subject.hlbtoplevel | Science | |
dc.description.peerreviewed | Peer Reviewed | |
dc.description.bitstreamurl | https://deepblue.lib.umich.edu/bitstream/2027.42/143675/1/cmdc201800027.pdf | |
dc.description.bitstreamurl | https://deepblue.lib.umich.edu/bitstream/2027.42/143675/2/cmdc201800027_am.pdf | |
dc.description.bitstreamurl | https://deepblue.lib.umich.edu/bitstream/2027.42/143675/3/cmdc201800027-sup-0001-misc_information.pdf | |
dc.identifier.doi | 10.1002/cmdc.201800027 | |
dc.identifier.source | ChemMedChem | |
dc.identifier.citedreference | C. W. Steele, S. A. Karim, J. D. Leach, P. Bailey, R. Upstill-Goddard, L. Rishi, M. Foth, S. Bryson, K. McDaid, Z. Wilson, Cancer Cell 2016, 29, 832 – 845. | |
dc.identifier.citedreference | J. Busch-Petersen, Curr. Top. Med. Chem. 2006, 6, 1345 – 1352. | |
dc.identifier.citedreference | M. Allegretti, R. Bertini, M. C. Cesta, C. Bizzarri, R. Di Bitondo, V. Di Cioccio, E. Galliera, V. Berdini, A. Topai, G. Zampella, J. Med. Chem. 2005, 48, 4312 – 4331. | |
dc.identifier.citedreference | L. Brandolini, L. Cristiano, A. Fidoamore, M. De Pizzol, E. Di Giacomo, T. M. Florio, G. Confalone, A. Galante, B. Cinque, E. Benedetti, P. A. Ruffini, M. G. Cifone, A. Giordano, M. Alecci, M. Allegretti, A. Cimini, Oncotarget 2015, 6, 43375 – 43394. | |
dc.identifier.citedreference | J. R. White, J. M. Lee, P. R. Young, R. P. Hertzberg, A. J. Jurewicz, M. A. Chaikin, K. Widdowson, J. J. Foley, L. D. Martin, D. E. Griswold, J. Biol. Chem. 1998, 273, 10095 – 10098. | |
dc.identifier.citedreference | R. B. Moss, S. J. Mistry, M. W. Konstan, J. M. Pilewski, E. Kerem, R. Tal-Singer, A. L. Lazaar, C. Investigators, J. Cystic Fibrosis 2013, 12, 241 – 248. | |
dc.identifier.citedreference | M. P. Dwyer, Y. Yu, J. Chao, C. Aki, J. Chao, P. Biju, V. Girijavallabhan, D. Rindgen, R. Bond, R. Mayer-Ezel, J. Med. Chem. 2006, 49, 7603 – 7606. | |
dc.identifier.citedreference | P. Nair, M. Gaga, E. Zervas, K. Alagha, F. Hargreave, P. O’byrne, P. Stryszak, L. Gann, J. Sadeh, P. Chanez, Clin. Exp. Allergy 2012, 42, 1097 – 1103. | |
dc.identifier.citedreference | R. Virtala, A. K. Ekman, L. Jansson, U. Westin, L.-O. Cardell, Clin. Exp. Allergy 2012, 42, 590 – 596. | |
dc.identifier.citedreference | D. Y. Maeda, A. M. Peck, A. D. Schuler, M. T. Quinn, L. N. Kirpotina, W. N. Wicomb, G. H. Fan, J. A. Zebala, J. Med. Chem. 2014, 57, 8378 – 8397. | |
dc.identifier.citedreference | X. Lu, J. W. Horner, E. Paul, X. Shang, P. Troncoso, P. Deng, S. Jiang, Q. Chang, D. J. Spring, P. Sharma, Nature 2017, 543, 728. | |
dc.identifier.citedreference | H. Ha, T. Bensman, H. Ho, P. M. Beringer, N. Neamati, Br. J. Pharmacol. 2014, 171, 1551 – 1565. | |
dc.identifier.citedreference | S. Peukert, Y. Sun, R. Zhang, B. Hurley, M. Sabio, X. Shen, C. Gray, J. Dzink-Fox, J. Tao, R. Cebula, S. Wattanasin, Bioorg. Med. Chem. Lett. 2008, 18, 1840 – 1844. | |
dc.identifier.citedreference | ||
dc.identifier.citedreference | H. Hajovsky, G. Hu, Y. Koen, D. Sarma, W. Cui, D. S. Moore, J. L. Staudinger, R. P. Hanzlik, Chem. Res. Toxicol. 2012, 25, 1955 – 1963; | |
dc.identifier.citedreference | M. Boyd, R. A. Neal, Drug Metab. Dispos. 1976, 4, 314 – 322. | |
dc.identifier.citedreference | P. E. Hansen, F. Duus, S. Bolvig, T. S. Jagodzinski, J. Mol. Struct. 1996, 378, 45 – 59. | |
dc.identifier.citedreference | ||
dc.identifier.citedreference | B. Kuhn, P. Mohr, M. Stahl, J. Med. Chem. 2010, 53, 2601 – 2611; | |
dc.identifier.citedreference | A. Alex, D. S. Millan, M. Perez, F. Wakenhut, G. A. Whitlock, MedChemComm 2011, 2, 669 – 674. | |
dc.identifier.citedreference | ADMET Predictor 8.0, SimulationsPlus: http://www.simulations-plus.com. | |
dc.identifier.citedreference | G. Vistoli, A. Pedretti, B. Testa, Drug Discovery Today 2008, 13, 285 – 294. | |
dc.identifier.citedreference | W. J. Egan, K. M. Merz, J. J. Baldwin, J. Med. Chem. 2000, 43, 3867 – 3877. | |
dc.identifier.citedreference | P. M. Murphy, M. Baggiolini, I. F. Charo, C. A. Hébert, R. Horuk, K. Matsushima, L. H. Miller, J. J. Oppenheim, C. A. Power, Pharmacol. Rev. 2000, 52, 145 – 176. | |
dc.identifier.citedreference | ||
dc.identifier.citedreference | M. Baggiolini, B. Dewald, B. Moser, Adv. Immunol. 1993, 55, 97 – 179; | |
dc.identifier.citedreference | L. Xu, D. Kelvin, G. Ye, D. Taub, A. Ben-Baruch, J. Oppenheim, J. Wang, J. Leukocyte Biol. 1995, 57, 335 – 342; | |
dc.identifier.citedreference | C. Murdoch, P. N. Monk, A. Finn, Cytokine 1999, 11, 704 – 712; | |
dc.identifier.citedreference | R. Horuk, A. W. Martin, Z.-X. Wang, L. Schweitzer, A. Gerassimides, H. Guo, Z.-h. Lu, J. Hesselgesser, H. D. Perez, J. Kim, J. Immunol. 1997, 158, 2882 – 2890. | |
dc.identifier.citedreference | C. Bizzarri, A. R. Beccari, R. Bertini, M. R. Cavicchia, S. Giorgini, M. Allegretti, Pharmacol. Ther. 2006, 112, 139 – 149. | |
dc.identifier.citedreference | F. Petersen, H.-D. Flad, E. Brandt, J. Immunol. 1994, 152, 2467 – 2478. | |
dc.identifier.citedreference | H. Ha, B. Debnath, N. Neamati, Theranostics 2017, 7, 1543 – 1588. | |
dc.identifier.citedreference | ||
dc.identifier.citedreference | V. M. Keatings, P. D. Collins, D. M. Scott, P. J. Barnes, Am. J. Respir. Crit. Care Med. 1996, 153, 530 – 534; | |
dc.identifier.citedreference | K. Reich, V. Blaschke, C. Maurer, U. Lippert, C. Neumann, C. Garbe, P. Middel, G. Westphal, J. Invest. Dermatol. 2001, 116, 319 – 329; | |
dc.identifier.citedreference | A. Kurdowska, J. M. Noble, I. S. Grant, C. R. Robertson, C. Haslett, S. C. Donnelly, Crit. Care Med. 2002, 30, 2335 – 2337; | |
dc.identifier.citedreference | M. K. Schwarz, T. N. Wells, Nat. Rev. Drug Discovery 2002, 1, 347 – 358; | |
dc.identifier.citedreference | C. Banks, A. Bateman, R. Payne, P. Johnson, N. Sheron, J. Pathol. 2003, 199, 28 – 35; | |
dc.identifier.citedreference | K. M. Beeh, O. Kornmann, R. Buhl, S. V. Culpitt, M. A. Giembycz, P. J. Barnes, CHEST J. 2003, 123, 1240 – 1247; | |
dc.identifier.citedreference | H. Erdem, S. Pay, M. Serdar, İ. Şimşek, A. Dinç, U. Muşabak, A. Pekel, M. Turan, Rheumatol. Int. 2005, 26, 162 – 167; | |
dc.identifier.citedreference | F. Lally, E. Smith, A. Filer, M. A. Stone, J. S. Shaw, G. B. Nash, C. D. Buckley, G. E. Rainger, Arthritis Rheum. 2005, 52, 3460 – 3469; | |
dc.identifier.citedreference | R. Chapman, J. Phillips, R. Hipkin, A. Curran, D. Lundell, J. Fine, Pharmacol. Ther. 2009, 121, 55 – 68; | |
dc.identifier.citedreference | L. Donnelly, P. Barnes, Drug Future 2011, 36, 465; | |
dc.identifier.citedreference | H. Xu, H. Lu, Z. Xu, L. Luan, C. Li, Y. Xu, K. Dong, J. Zhang, X. Li, Y. Li, G. Liu, S. Gong, Y. G. Zhao, A. Liu, Y. Zhang, W. Zhang, X. Cai, J. N. Xiang, J. D. Elliott, X. Lin, ACS Med. Chem. Lett. 2016, 7, 397 – 402. | |
dc.identifier.citedreference | ||
dc.identifier.citedreference | M. Clarke, T. Jamieson, C. Steele, M. Olson, M. Samuel, S. Das, O. Sansom, R. Nibbs, Immunology 2012, 137, 190; | |
dc.identifier.citedreference | L. Han, B. Jiang, H. Wu, X. Wang, X. Tang, J. Huang, J. Zhu, Med. Oncol. 2012, 29, 2466 – 2472; | |
dc.identifier.citedreference | T. Jamieson, M. Clarke, C. W. Steele, M. S. Samuel, J. Neumann, A. Jung, D. Huels, M. F. Olson, S. Das, R. J. Nibbs, J. Clin. Invest. 2012, 122, 3127; | |
dc.identifier.citedreference | L. Gong, A. M. Cumpian, M. S. Caetano, C. E. Ochoa, M. M. De la Garza, D. J. Lapid, S. G. Mirabolfathinejad, B. F. Dickey, Q. Zhou, S. J. Moghaddam, Mol. Cancer 2013, 12, 154; | |
dc.identifier.citedreference | H. Katoh, D. Wang, T. Daikoku, H. Sun, S. K. Dey, R. N. DuBois, Cancer Cell 2013, 24, 631 – 644. | |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.