The Use of Conformational Restriction in Medicinal Chemistry

Author(s): Pedro de Sena M. Pinheiro, Daniel A. Rodrigues, Rodolfo do Couto Maia, Sreekanth Thota, Carlos A.M. Fraga*

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 19 , 2019


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Graphical Abstract:


Abstract:

During the early preclinical phase, from hit identification and optimization to a lead compound, several medicinal chemistry strategies can be used to improve potency and/or selectivity. The conformational restriction is one of these approaches. It consists of introducing some specific structural constraints in a lead candidate to reduce the overall number of possible conformations in order to favor the adoption of a bioactive conformation and, as a consequence, molecular recognition by the target receptor. In this work, we focused on the application of the conformational restriction strategy in the last five years for the optimization of hits and/or leads of several important classes of therapeutic targets in the drug discovery field. Thus, we recognize the importance of several kinase inhibitors to the current landscape of drug development for cancer therapy and the use of G-protein Coupled Receptor (GPCR) modulators. Several other targets are also highlighted, such as the class of epigenetic drugs. Therefore, the possibility of exploiting conformational restriction as a tool to increase the potency and selectivity and promote changes in the intrinsic activity of some ligands intended to act on many different targets makes this strategy of structural modification valuable for the discovery of novel drug candidates.

Keywords: Restriction, Constraint, Annulation, Cyclization, Kinase, G-protein coupled receptor, Hit-to-lead, Thermodynamics.

[1]
Koshland, D.E. The key–lock theory and the induced fit theory. Angew. Chem. Int. Ed. Engl., 1995, 33(23‐24), 2375-2378.
[http://dx.doi.org/10.1002/anie.199423751]
[2]
Klebe, G. Applying thermodynamic profiling in lead finding and optimization. Nat. Rev. Drug Discov., 2015, 14(2), 95-110.
[http://dx.doi.org/10.1038/nrd4486] [PMID: 25614222]
[3]
Reynolds, C.H.; Holloway, M.K. Thermodynamics of ligand binding and efficiency. ACS Med. Chem. Lett., 2011, 2(6), 433-437.
[http://dx.doi.org/10.1021/ml200010k] [PMID: 24900326]
[4]
Wienen-Schmidt, B.; Jonker, H.R.A.; Wulsdorf, T.; Gerber, H.D.; Saxena, K.; Kudlinzki, D.; Sreeramulu, S.; Parigi, G.; Luchinat, C.; Heine, A.; Schwalbe, H.; Klebe, G. Paradoxically, Most flexible ligand binds most entropy-favored: intriguing impact of ligand flexibility and solvation on drug-kinase binding. J. Med. Chem., 2018, 61(14), 5922-5933.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00105] [PMID: 29909615]
[5]
Ferenczy, G.G.; Keserũ, G.M. Thermodynamics guided lead discovery and optimization. Drug Discov. Today, 2010, 15(21-22), 919-932.
[http://dx.doi.org/10.1016/j.drudis.2010.08.013] [PMID: 20801227]
[6]
Fang, Z.; Song, Y.; Zhan, P.; Zhang, Q.; Liu, X. Conformational restriction: An effective tactic in ‘follow-on’-based drug discovery. Future Med. Chem., 2014, 6(8), 885-901.
[http://dx.doi.org/10.4155/fmc.14.50] [PMID: 24962281]
[7]
Cohen, P.; Alessi, D.R. Kinase drug discovery--what’s next in the field? ACS Chem. Biol., 2013, 8(1), 96-104.
[http://dx.doi.org/10.1021/cb300610s] [PMID: 23276252]
[8]
Pao, W.; Chmielecki, J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat. Rev. Cancer, 2010, 10(11), 760-774.
[http://dx.doi.org/10.1038/nrc2947] [PMID: 20966921]
[9]
Lurje, G.; Lenz, H.J. EGFR signaling and drug discovery. Oncology, 2009, 77(6), 400-410.
[http://dx.doi.org/10.1159/000279388] [PMID: 20130423]
[10]
Engel, J.; Lategahn, J.; Rauh, D. Hope and disappointment: covalent inhibitors to overcome drug resistance in non-small cell lung cancer. ACS Med. Chem. Lett., 2015, 7(1), 2-5.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00475] [PMID: 26819655]
[11]
Holohan, C.; Van Schaeybroeck, S.; Longley, D.B.; Johnston, P.G. Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer, 2013, 13(10), 714-726.
[http://dx.doi.org/10.1038/nrc3599] [PMID: 24060863]
[12]
Zhou, W.; Ercan, D.; Chen, L.; Yun, C.H.; Li, D.; Capelletti, M.; Cortot, A.B.; Chirieac, L.; Iacob, R.E.; Padera, R.; Engen, J.R.; Wong, K.K.; Eck, M.J.; Gray, N.S.; Jänne, P.A. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature, 2009, 462(7276), 1070-1074.
[http://dx.doi.org/10.1038/nature08622] [PMID: 20033049]
[13]
Chang, S.; Zhang, L.; Xu, S.; Luo, J.; Lu, X.; Zhang, Z.; Xu, T.; Liu, Y.; Tu, Z.; Xu, Y.; Ren, X.; Geng, M.; Ding, J.; Pei, D.; Ding, K. Design, synthesis, and biological evaluation of novel conformationally constrained inhibitors targeting epidermal growth factor receptor threonine790 → methionine790 mutant. J. Med. Chem., 2012, 55(6), 2711-2723.
[http://dx.doi.org/10.1021/jm201591k] [PMID: 22339342]
[14]
Xu, S.; Zhang, L.; Chang, S.; Luo, J.; Lu, X.; Tu, Z.; Liu, Y.; Zhang, Z.; Xu, Y.; Ren, X.; Ding, K. Design, synthesis and biological evaluation of new molecules inhibiting epidermal growth factor receptor threonine790 --> methionine790 mutant. MedChemComm, 2012, 3(9), 1155-1159.
[http://dx.doi.org/10.1039/c2md20078c]
[15]
Xu, T.; Zhang, L.; Xu, S.; Yang, C.Y.; Luo, J.; Ding, F.; Lu, X.; Liu, Y.; Tu, Z.; Li, S.; Pei, D.; Cai, Q.; Li, H.; Ren, X.; Wang, S.; Ding, K. Pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives as selective inhibitors of EGFR threonine790 to methionine790 (T790M) mutants. Angew. Chem. Int. Ed. Engl., 2013, 52(32), 8387-8390.
[http://dx.doi.org/10.1002/anie.201302313] [PMID: 23804305]
[16]
Ge, Y.; Jin, Y.; Wang, C.; Zhang, J.; Tang, Z.; Peng, J.; Liu, K.; Li, Y.; Zhou, Y.; Ma, X. Discovery of novel bruton’s tyrosine kinase (BTK) inhibitors bearing a N,9-Diphenyl-9H-purin-2-amine scaffold. ACS Med. Chem. Lett., 2016, 7(12), 1050-1055.
[http://dx.doi.org/10.1021/acsmedchemlett.6b00235] [PMID: 27994736]
[17]
Xing, L.; Huang, A. Bruton’s TK inhibitors: structural insights and evolution of clinical candidates. Future Med. Chem., 2014, 6(6), 675-695.
[http://dx.doi.org/10.4155/fmc.14.24] [PMID: 24895895]
[18]
Whang, J.A.; Chang, B.Y. Bruton’s tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Drug Discov. Today, 2014, 19(8), 1200-1204.
[http://dx.doi.org/10.1016/j.drudis.2014.03.028] [PMID: 24721226]
[19]
Hendriks, R.W.; Yuvaraj, S.; Kil, L.P. Targeting Bruton’s tyrosine kinase in B cell malignancies. Nat. Rev. Cancer, 2014, 14(4), 219-232.
[http://dx.doi.org/10.1038/nrc3702] [PMID: 24658273]
[20]
Barf, T.; Kaptein, A. Irreversible protein kinase inhibitors: Balancing the benefits and risks. J. Med. Chem., 2012, 55(14), 6243-6262.
[http://dx.doi.org/10.1021/jm3003203] [PMID: 22621397]
[21]
Huang, Z.; Zhang, Q.; Yan, L.; Zhong, G.; Zhang, L.; Tan, X.; Wang, Y. Approaching the active conformation of 1,3-diaminopyrimidine based covalent inhibitors of Bruton’s tyrosine kinase for treatment of Rheumatoid arthritis. Bioorg. Med. Chem. Lett., 2016, 26(8), 1954-1957.
[http://dx.doi.org/10.1016/j.bmcl.2016.03.011] [PMID: 26976214]
[22]
Bryan, M.C.; Burdick, D.J.; Chan, B.K.; Chen, Y.; Clausen, S.; Dotson, J.; Eigenbrot, C.; Elliott, R.; Hanan, E.J.; Heald, R.; Jackson, P.; La, H.; Lainchbury, M.; Malek, S.; Mann, S.E.; Purkey, H.E.; Schaefer, G.; Schmidt, S.; Seward, E.; Sideris, S.; Wang, S.; Yen, I.; Yu, C.; Heffron, T.P. Pyridones as highly selective, noncovalent inhibitors of T790M double mutants of EGFR. ACS Med. Chem. Lett., 2015, 7(1), 100-104.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00428] [PMID: 26819674]
[23]
Baskin, R.; Majumder, A.; Sayeski, P.P. The recent medicinal chemistry development of JAK2 tyrosine kinase small molecule inhibitors. Curr. Med. Chem., 2010, 17(36), 4551-4558.
[http://dx.doi.org/10.2174/092986710794182953] [PMID: 21062251]
[24]
Sonbol, M.B.; Firwana, B.; Zarzour, A.; Morad, M.; Rana, V.; Tiu, R.V. Comprehensive review of JAK inhibitors in myeloproliferative neoplasms. Ther. Adv. Hematol., 2013, 4(1), 15-35.
[http://dx.doi.org/10.1177/2040620712461047] [PMID: 23610611]
[25]
Levine, R.L.; Pardanani, A.; Tefferi, A.; Gilliland, D.G. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat. Rev. Cancer, 2007, 7(9), 673-683.
[http://dx.doi.org/10.1038/nrc2210] [PMID: 17721432]
[26]
Siu, T.; Kozina, E.S.; Jung, J.; Rosenstein, C.; Mathur, A.; Altman, M.D.; Chan, G.; Xu, L.; Bachman, E.; Mo, J.R.; Bouthillette, M.; Rush, T.; Dinsmore, C.J.; Marshall, C.G.; Young, J.R. The discovery of tricyclic pyridone JAK2 inhibitors. Part 1: hit to lead. Bioorg. Med. Chem. Lett., 2010, 20(24), 7421-7425.
[http://dx.doi.org/10.1016/j.bmcl.2010.10.031] [PMID: 21044843]
[27]
Quintás-Cardama, A.; Kantarjian, H.; Cortes, J.; Verstovsek, S. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat. Rev. Drug Discov., 2011, 10(2), 127-140.
[http://dx.doi.org/10.1038/nrd3264] [PMID: 21283107]
[28]
de Vicente, J.; Lemoine, R.; Bartlett, M.; Hermann, J.C.; Hekmat-Nejad, M.; Henningsen, R.; Jin, S.; Kuglstatter, A.; Li, H.; Lovey, A.J.; Menke, J.; Niu, L.; Patel, V.; Petersen, A.; Setti, L.; Shao, A.; Tivitmahaisoon, P.; Vu, M.D.; Soth, M. Scaffold hopping towards potent and selective JAK3 inhibitors: discovery of novel C-5 substituted pyrrolopyrazines. Bioorg. Med. Chem. Lett., 2014, 24(21), 4969-4975.
[http://dx.doi.org/10.1016/j.bmcl.2014.09.031] [PMID: 25262541]
[29]
Gehringer, M.; Pfaffenrot, E.; Bauer, S.; Laufer, S.A. Design and synthesis of tricyclic JAK3 inhibitors with picomolar affinities as novel molecular probes. ChemMedChem, 2014, 9(2), 277-281.
[http://dx.doi.org/10.1002/cmdc.201300520] [PMID: 24403205]
[30]
Vivanco, I.; Sawyers, C.L. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer, 2002, 2(7), 489-501.
[http://dx.doi.org/10.1038/nrc839] [PMID: 12094235]
[31]
Thorpe, L.M.; Yuzugullu, H.; Zhao, J.J. PI3K in cancer: Divergent roles of isoforms, modes of activation and therapeutic targeting. Nat. Rev. Cancer, 2015, 15(1), 7-24.
[http://dx.doi.org/10.1038/nrc3860] [PMID: 25533673]
[32]
Andrs, M.; Korabecny, J.; Jun, D.; Hodny, Z.; Bartek, J.; Kuca, K. Phosphatidylinositol 3-Kinase (PI3K) and Phosphatidylinositol 3-Kinase-related Kinase (PIKK) inhibitors: importance of the morpholine ring. J. Med. Chem., 2015, 58(1), 41-71.
[http://dx.doi.org/10.1021/jm501026z] [PMID: 25387153]
[33]
Liu, P.; Cheng, H.; Roberts, T.M.; Zhao, J.J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov., 2009, 8(8), 627-644.
[http://dx.doi.org/10.1038/nrd2926] [PMID: 19644473]
[34]
Wang, X.; Ding, J.; Meng, L.H. PI3K isoform-selective inhibitors: Next-generation targeted cancer therapies. Acta Pharmacol. Sin., 2015, 36(10), 1170-1176.
[http://dx.doi.org/10.1038/aps.2015.71] [PMID: 26364801]
[35]
Fruman, D.A.; Rommel, C. PI3K and cancer: Lessons, challenges and opportunities. Nat. Rev. Drug Discov., 2014, 13(2), 140-156.
[http://dx.doi.org/10.1038/nrd4204] [PMID: 24481312]
[36]
Paul, J.; Soujon, M.; Wengner, A.M.; Zitzmann-Kolbe, S.; Sturz, A.; Haike, K.; Keng Magdalene, K.H.; Tan, S.H.; Lange, M.; Tan, S.Y.; Mumberg, D.; Lim, S.T.; Ziegelbauer, K.; Liu, N. Simultaneous inhibition of PI3Kδ and PI3Kα induces ABC-DLBCL regression by blocking BCR-dependent and -independent activation of NF-κB and AKT. Cancer Cell, 2017, 31(1), 64-78.
[http://dx.doi.org/10.1016/j.ccell.2016.12.003] [PMID: 28073005]
[37]
Martínez González, S.; Hernández, A.I.; Varela, C.; Rodríguez-Arístegui, S.; Lorenzo, M.; Rodríguez, A.; Rivero, V.; Martín, J.I.; Saluste, C.G.; Ramos-Lima, F.; Cendón, E.; Cebrián, D.; Aguirre, E.; Gomez-Casero, E.; Albarrán, M.; Alfonso, P.; García-Serelde, B.; Oyarzabal, J.; Rabal, O.; Mulero, F.; Gonzalez-Granda, T.; Link, W.; Fominaya, J.; Barbacid, M.; Bischoff, J.R.; Pizcueta, P.; Pastor, J. Identification of ETP-46321, a potent and orally bioavailable PI3K α, δ inhibitor. Bioorg. Med. Chem. Lett., 2012, 22(10), 3460-3466.
[http://dx.doi.org/10.1016/j.bmcl.2012.03.090] [PMID: 22520259]
[38]
Martínez González, S.; Rodríguez-Arístegui, S.; Hernández, A.I.; Varela, C.; González Cantalapiedra, E.; Álvarez, R.M.; Rodríguez Hergueta, A.; Bischoff, J.R.; Albarrán, M.I.; Cebriá, A.; Cendón, E.; Cebrián, D.; Alfonso, P.; Pastor, J. Generation of tricyclic imidazo[1,2-a]pyrazines as novel PI3K inhibitors by application of a conformational restriction strategy. Bioorg. Med. Chem. Lett., 2017, 27(11), 2536-2543.
[http://dx.doi.org/10.1016/j.bmcl.2017.03.090] [PMID: 28404374]
[39]
Ma, X.; Fang, F.; Tao, Q.; Shen, L.; Zhong, G.; Qiao, T.; Lv, X.; Li, J. Conformationally restricted quinazolone derivatives as PI3Kδ-selective inhibitors: The design, synthesis and biological evaluation. MedChemComm, 2019, 10(3), 413-420.
[http://dx.doi.org/10.1039/C8MD00556G] [PMID: 30996859]
[40]
Somoza, J.R.; Koditek, D.; Villaseñor, A.G.; Novikov, N.; Wong, M.H.; Liclican, A.; Xing, W.; Lagpacan, L.; Wang, R.; Schultz, B.E.; Papalia, G.A.; Samuel, D.; Lad, L.; McGrath, M.E. Structural, biochemical, and biophysical characterization of idelalisib binding to phosphoinositide 3-kinase δ. J. Biol. Chem., 2015, 290(13), 8439-8446.
[http://dx.doi.org/10.1074/jbc.M114.634683] [PMID: 25631052]
[41]
Busillo, J.M.; Benovic, J.L. Regulation of CXCR4 signaling. Biochim. Biophys. Acta, 2007, 1768(4), 952-963.
[http://dx.doi.org/10.1016/j.bbamem.2006.11.002] [PMID: 17169327]
[42]
Epstein, R.J. The CXCL12-CXCR4 chemotactic pathway as a target of adjuvant breast cancer therapies. Nat. Rev. Cancer, 2004, 4(11), 901-909.
[http://dx.doi.org/10.1038/nrc1473] [PMID: 15516962]
[43]
Burger, J.A.; Kipps, T.J. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood, 2006, 107(5), 1761-1767.
[http://dx.doi.org/10.1182/blood-2005-08-3182] [PMID: 16269611]
[44]
Skerlj, R.T.; Bridger, G.J.; Kaller, A.; McEachern, E.J.; Crawford, J.B.; Zhou, Y.; Atsma, B.; Langille, J.; Nan, S.; Veale, D.; Wilson, T.; Harwig, C.; Hatse, S.; Princen, K.; De Clercq, E.; Schols, D. Discovery of novel small molecule orally bioavailable C-X-C chemokine receptor 4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication. J. Med. Chem., 2010, 53(8), 3376-3388.
[http://dx.doi.org/10.1021/jm100073m] [PMID: 20297846]
[45]
Skerlj, R.; Bridger, G.; McEachern, E.; Harwig, C.; Smith, C.; Wilson, T.; Veale, D.; Yee, H.; Crawford, J.; Skupinska, K.; Wauthy, R.; Yang, W.; Zhu, Y.; Bogucki, D.; Di Fluri, M.; Langille, J.; Huskens, D.; De Clercq, E.; Schols, D. Synthesis and SAR of novel CXCR4 antagonists that are potent inhibitors of T tropic (X4) HIV-1 replication. Bioorg. Med. Chem. Lett., 2011, 21(1), 262-266.
[http://dx.doi.org/10.1016/j.bmcl.2010.11.023] [PMID: 21109432]
[46]
Truax, V.M.; Zhao, H.; Katzman, B.M.; Prosser, A.R.; Alcaraz, A.A.; Saindane, M.T.; Howard, R.B.; Culver, D.; Arrendale, R.F.; Gruddanti, P.R.; Evers, T.J.; Natchus, M.G.; Snyder, J.P.; Liotta, D.C.; Wilson, L.J. Discovery of tetrahydroisoquinoline-based CXCR4 antagonists. ACS Med. Chem. Lett., 2013, 4(11), 1025-1030.
[http://dx.doi.org/10.1021/ml400183q] [PMID: 24936240]
[47]
Jecs, E.; Miller, E.J.; Wilson, R.J.; Nguyen, H.H.; Tahirovic, Y.A.; Katzman, B.M.; Truax, V.M.; Kim, M.B.; Kuo, K.M.; Wang, T.; Sum, C.S.; Cvijic, M.E.; Schroeder, G.M.; Wilson, L.J.; Liotta, D.C. Synthesis of novel tetrahydroisoquinoline CXCR4 antagonists with rigidified side-chains. ACS Med. Chem. Lett., 2017, 9(2), 89-93.
[http://dx.doi.org/10.1021/acsmedchemlett.7b00406] [PMID: 29456793]
[48]
Tanaka, H.; Yoshida, S.; Oshima, H.; Minoura, H.; Negoro, K.; Yamazaki, T.; Sakuda, S.; Iwasaki, F.; Matsui, T.; Shibasaki, M. Chronic treatment with novel GPR40 agonists improve whole-body glucose metabolism based on the glucose-dependent insulin secretion. J. Pharmacol. Exp. Ther., 2013, 346(3), 443-452.
[http://dx.doi.org/10.1124/jpet.113.206466] [PMID: 23853170]
[49]
Mancini, A.D.; Poitout, V. The fatty acid receptor FFA1/GPR40 a decade later: how much do we know? Trends Endocrinol. Metab., 2013, 24(8), 398-407.
[http://dx.doi.org/10.1016/j.tem.2013.03.003] [PMID: 23631851]
[50]
Rodrigues, D.A.; Pinheiro, P.S.M.; Ferreira, T.T.D.S.C.; Thota, S.; Fraga, C.A.M. Structural basis for the agonist action at free fatty acid receptor 1 (FFA1R or GPR40). Chem. Biol. Drug Des., 2018, 91(3), 668-680.
[http://dx.doi.org/10.1111/cbdd.13131] [PMID: 29068547]
[51]
Wang, Y.; Liu, J.J.; Dransfield, P.J.; Zhu, L.; Wang, Z.; Du, X.; Jiao, X.; Su, Y.; Li, A.R.; Brown, S.P.; Kasparian, A.; Vimolratana, M.; Yu, M.; Pattaropong, V.; Houze, J.B.; Swaminath, G.; Tran, T.; Nguyen, K.; Guo, Q.; Zhang, J.; Zhuang, R.; Li, F.; Miao, L.; Bartberger, M.D.; Correll, T.L.; Chow, D.; Wong, S.; Luo, J.; Lin, D.C.; Medina, J.C. Discovery and optimization of potent GPR40 full agonists containing tricyclic spirocycles. ACS Med. Chem. Lett., 2013, 4(6), 551-555.
[http://dx.doi.org/10.1021/ml300427u] [PMID: 24900707]
[52]
Takano, R.; Yoshida, M.; Inoue, M.; Honda, T.; Nakashima, R.; Matsumoto, K.; Yano, T.; Ogata, T.; Watanabe, N.; Hirouchi, M.; Yoneyama, T.; Ito, S.; Toda, N. Discovery of DS-1558: A potent and orally bioavailable GPR40 agonist. ACS Med. Chem. Lett., 2015, 6(3), 266-270.
[http://dx.doi.org/10.1021/ml500391n] [PMID: 25815144]
[53]
Ohishi, T.; Yoshida, S. The therapeutic potential of GPR119 agonists for type 2 diabetes. Expert Opin. Investig. Drugs, 2012, 21(3), 321-328.
[http://dx.doi.org/10.1517/13543784.2012.657797] [PMID: 22292451]
[54]
Carpino, P.A.; Goodwin, B. Diabetes area participation analysis: a review of companies and targets described in the 2008 - 2010 patent literature. Expert Opin. Ther. Pat., 2010, 20(12), 1627-1651.
[http://dx.doi.org/10.1517/13543776.2010.533171] [PMID: 21083519]
[55]
Futatsugi, K.; Mascitti, V.; Guimarães, C.R.; Morishita, N.; Cai, C.; DeNinno, M.P.; Gao, H.; Hamilton, M.D.; Hank, R.; Harris, A.R.; Kung, D.W.; Lavergne, S.Y.; Lefker, B.A.; Lopaze, M.G.; McClure, K.F.; Munchhof, M.J.; Preville, C.; Robinson, R.P.; Wright, S.W.; Bonin, P.D.; Cornelius, P.; Chen, Y.; Kalgutkar, A.S. From partial to full agonism: identification of a novel 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole as a full agonist of the human GPR119 receptor. Bioorg. Med. Chem. Lett., 2013, 23(1), 194-197.
[http://dx.doi.org/10.1016/j.bmcl.2012.10.119] [PMID: 23177788]
[56]
Scott, J.S.; Brocklehurst, K.J.; Brown, H.S.; Clarke, D.S.; Coe, H.; Groombridge, S.D.; Laber, D.; MacFaul, P.A.; McKerrecher, D.; Schofield, P. Conformational restriction in a series of GPR119 agonists: differences in pharmacology between mouse and human. Bioorg. Med. Chem. Lett., 2013, 23(11), 3175-3179.
[http://dx.doi.org/10.1016/j.bmcl.2013.04.006] [PMID: 23628336]
[57]
Koshizawa, T.; Morimoto, T.; Watanabe, G.; Watanabe, T.; Yamasaki, N.; Sawada, Y.; Fukuda, T.; Okuda, A.; Shibuya, K.; Ohgiya, T. Optimization of a novel series of potent and orally bioavailable GPR119 agonists. Bioorg. Med. Chem. Lett., 2017, 27(15), 3249-3253.
[http://dx.doi.org/10.1016/j.bmcl.2017.06.034] [PMID: 28648463]
[58]
Calo’, G.; Guerrini, R.; Rizzi, A.; Salvadori, S.; Regoli, D. Pharmacology of nociceptin and its receptor: a novel therapeutic target. Br. J. Pharmacol., 2000, 129(7), 1261-1283.
[http://dx.doi.org/10.1038/sj.bjp.0703219] [PMID: 10742280]
[59]
Rivière, P.J. Peripheral kappa-opioid agonists for visceral pain. Br. J. Pharmacol., 2004, 141(8), 1331-1334.
[http://dx.doi.org/10.1038/sj.bjp.0705763] [PMID: 15051626]
[60]
Köhler, J.; Bergander, K.; Fabian, J.; Schepmann, D.; Wünsch, B. Enantiomerically pure 1,3-dioxanes as highly selective NMDA and σ1 receptor ligands. J. Med. Chem., 2012, 55(20), 8953-8957.
[http://dx.doi.org/10.1021/jm301166m] [PMID: 23013229]
[61]
Galla, F.; Bourgeois, C.; Lehmkuhl, K.; Schepmann, D.; Soeberdt, M.; Lotts, T.; Abels, C.; Stander, S.; Wunsch, B. Effects of polar [small kappa] receptor agonists designed for the periphery on ATP-induced Ca2+ release from keratinocytes. MedChemComm, 2016, 7(2), 317-326.
[http://dx.doi.org/10.1039/C5MD00414D]
[62]
Gubellini, P.; Pisani, A.; Centonze, D.; Bernardi, G.; Calabresi, P. Metabotropic glutamate receptors and striatal synaptic plasticity: implications for neurological diseases. Prog. Neurobiol., 2004, 74(5), 271-300.
[http://dx.doi.org/10.1016/j.pneurobio.2004.09.005] [PMID: 15582223]
[63]
Caraci, F.; Battaglia, G.; Sortino, M.A.; Spampinato, S.; Molinaro, G.; Copani, A.; Nicoletti, F.; Bruno, V. Metabotropic glutamate receptors in neurodegeneration/neuroprotection: still a hot topic? Neurochem. Int., 2012, 61(4), 559-565.
[http://dx.doi.org/10.1016/j.neuint.2012.01.017] [PMID: 22306345]
[64]
Goudet, C.; Magnaghi, V.; Landry, M.; Nagy, F.; Gereau, R.W., IV; Pin, J.P. Metabotropic receptors for glutamate and GABA in pain. Brain Res. Brain Res. Rev., 2009, 60(1), 43-56.
[http://dx.doi.org/10.1016/j.brainresrev.2008.12.007] [PMID: 19146876]
[65]
Pitsikas, N. The metabotropic glutamate receptors: potential drug targets for the treatment of anxiety disorders? Eur. J. Pharmacol., 2014, 723, 181-184.
[http://dx.doi.org/10.1016/j.ejphar.2013.12.019] [PMID: 24361306]
[66]
Pomierny-Chamioło, L.; Rup, K.; Pomierny, B.; Niedzielska, E.; Kalivas, P.W.; Filip, M. Metabotropic glutamatergic receptors and their ligands in drug addiction. Pharmacol. Ther., 2014, 142(3), 281-305.
[http://dx.doi.org/10.1016/j.pharmthera.2013.12.012] [PMID: 24362085]
[67]
Nickols, H.H.; Conn, P.J. Development of allosteric modulators of GPCRs for treatment of CNS disorders. Neurobiol. Dis., 2014, 61, 55-71.
[http://dx.doi.org/10.1016/j.nbd.2013.09.013] [PMID: 24076101]
[68]
Goudet, C.; Binet, V.; Prezeau, L.; Pin, J-P. Allosteric modulators of class-C G-protein-coupled receptors open new possibilities for therapeutic application. Drug Discov. Today Ther. Strateg., 2004, 1(1), 125-133.
[http://dx.doi.org/10.1016/j.ddstr.2004.08.017]
[69]
Engers, D.W.; Field, J.R.; Le, U.; Zhou, Y.; Bolinger, J.D.; Zamorano, R.; Blobaum, A.L.; Jones, C.K.; Jadhav, S.; Weaver, C.D.; Conn, P.J.; Lindsley, C.W.; Niswender, C.M.; Hopkins, C.R. Discovery, synthesis, and structure-activity relationship development of a series of N-(4-acetamido)phenylpicolinamides as positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)) with CNS exposure in rats. J. Med. Chem., 2011, 54(4), 1106-1110.
[http://dx.doi.org/10.1021/jm101271s] [PMID: 21247167]
[70]
Gomez-Santacana, X.; Rovira, X.; Dalton, J.A.; Goudet, C.; Pin, J.P.; Gorostiza, P.; Giraldo, J.; Llebaria, A. A double effect molecular switch leads to a novel potent negative allosteric modulator of metabotropic glutamate receptor 5. MedChemComm, 2014, 5(10), 1548-1554.
[http://dx.doi.org/10.1039/C4MD00208C]
[71]
Witt, O.; Deubzer, H.E.; Milde, T.; Oehme, I. HDAC family: What are the cancer relevant targets? Cancer Lett., 2009, 277(1), 8-21.
[http://dx.doi.org/10.1016/j.canlet.2008.08.016] [PMID: 18824292]
[72]
Johnstone, R.W. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat. Rev. Drug Discov., 2002, 1(4), 287-299.
[http://dx.doi.org/10.1038/nrd772] [PMID: 12120280]
[73]
Rodrigues, D.A.; Thota, S.; Fraga, C.A. Beyond the selective inhibition of histone deacetylase 6. Mini Rev. Med. Chem., 2016, 16(14), 1175-1184.
[http://dx.doi.org/10.2174/1389557516666160428115959] [PMID: 27121714]
[74]
Chen, K.; Zhang, X.; Wu, Y-D.; Wiest, O. Inhibition and mechanism of HDAC8 revisited. J. Am. Chem. Soc., 2014, 136(33), 11636-11643.
[http://dx.doi.org/10.1021/ja501548p] [PMID: 25060069]
[75]
Hailu, G.S.; Robaa, D.; Forgione, M.; Sippl, W.; Rotili, D.; Mai, A. Lysine deacetylase inhibitors in parasites: past, present, and future perspectives. J. Med. Chem., 2017, 60(12), 4780-4804.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01595] [PMID: 28241112]
[76]
Taha, T.Y.; Aboukhatwa, S.M.; Knopp, R.C.; Ikegaki, N.; Abdelkarim, H.; Neerasa, J.; Lu, Y.; Neelarapu, R.; Hanigan, T.W.; Thatcher, G.R.J.; Petukhov, P.A. Design, synthesis, and biological evaluation of tetrahydroisoquinoline-based histone deacetylase 8 selective inhibitors. ACS Med. Chem. Lett., 2017, 8(8), 824-829.
[http://dx.doi.org/10.1021/acsmedchemlett.7b00126] [PMID: 28835796]
[77]
Viré, E.; Brenner, C.; Deplus, R.; Blanchon, L.; Fraga, M.; Didelot, C.; Morey, L.; Van Eynde, A.; Bernard, D.; Vanderwinden, J.M.; Bollen, M.; Esteller, M.; Di Croce, L.; de Launoit, Y.; Fuks, F. The Polycomb group protein EZH2 directly controls DNA methylation. Nature, 2006, 439(7078), 871-874.
[http://dx.doi.org/10.1038/nature04431] [PMID: 16357870]
[78]
Simon, J.A.; Lange, C.A. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat. Res., 2008, 647(1-2), 21-29.
[http://dx.doi.org/10.1016/j.mrfmmm.2008.07.010] [PMID: 18723033]
[79]
Kung, P.P.; Rui, E.; Bergqvist, S.; Bingham, P.; Braganza, J.; Collins, M.; Cui, M.; Diehl, W.; Dinh, D.; Fan, C.; Fantin, V.R.; Gukasyan, H.J.; Hu, W.; Huang, B.; Kephart, S.; Krivacic, C.; Kumpf, R.A.; Li, G.; Maegley, K.A.; McAlpine, I.; Nguyen, L.; Ninkovic, S.; Ornelas, M.; Ryskin, M.; Scales, S.; Sutton, S.; Tatlock, J.; Verhelle, D.; Wang, F.; Wells, P.; Wythes, M.; Yamazaki, S.; Yip, B.; Yu, X.; Zehnder, L.; Zhang, W.G.; Rollins, R.A.; Edwards, M. Design and synthesis of pyridone-containing 3,4-dihydroisoquinoline-1(2H)-ones as a novel class of enhancer of zeste homolog 2 (EZH2) inhibitors. J. Med. Chem., 2016, 59(18), 8306-8325.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00515] [PMID: 27512831]
[80]
Stavropoulos, P.; Hoelz, A. Lysine-specific demethylase 1 as a potential therapeutic target. Expert Opin. Ther. Targets, 2007, 11(6), 809-820.
[http://dx.doi.org/10.1517/14728222.11.6.809] [PMID: 17504018]
[81]
McAllister, T.E.; England, K.S.; Hopkinson, R.J.; Brennan, P.E.; Kawamura, A.; Schofield, C.J. Recent progress in histone demethylase inhibitors. J. Med. Chem., 2016, 59(4), 1308-1329.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01758] [PMID: 26710088]
[82]
Sorna, V.; Theisen, E.R.; Stephens, B.; Warner, S.L.; Bearss, D.J.; Vankayalapati, H.; Sharma, S. High-throughput virtual screening identifies novel N′-(1-phenylethylidene)-benzohydrazides as potent, specific, and reversible LSD1 inhibitors. J. Med. Chem., 2013, 56(23), 9496-9508.
[http://dx.doi.org/10.1021/jm400870h] [PMID: 24237195]
[83]
Zhou, Y.; Li, Y.; Wang, W.J.; Xiang, P.; Luo, X.M.; Yang, L.; Yang, S.Y.; Zhao, Y.L. Synthesis and biological evaluation of novel (E)-N′-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides as potent LSD1 inhibitors. Bioorg. Med. Chem. Lett., 2016, 26(18), 4552-4557.
[http://dx.doi.org/10.1016/j.bmcl.2015.06.054] [PMID: 27524309]
[84]
Bursavich, M.G.; Harrison, B.A.; Blain, J.F. Gamma secretase modulators: New alzheimer’s drugs on the horizon? J. Med. Chem., 2016, 59(16), 7389-7409.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01960] [PMID: 27007185]
[85]
Wolfe, M.S. gamma-Secretase modulators. Curr. Alzheimer Res., 2007, 4(5), 571-573.
[http://dx.doi.org/10.2174/156720507783018299] [PMID: 18220525]
[86]
Peretto, I.; La Porta, E. Gamma-secretase modulation and its promise for Alzheimer’s disease: A medicinal chemistry perspective. Curr. Top. Med. Chem., 2008, 8(1), 38-46.
[http://dx.doi.org/10.2174/156802608783334097] [PMID: 18220931]
[87]
Golde, T.E.; Koo, E.H.; Felsenstein, K.M.; Osborne, B.A.; Miele, L. γ-Secretase inhibitors and modulators. Biochim. Biophys. Acta, 2013, 1828(12), 2898-2907.
[http://dx.doi.org/10.1016/j.bbamem.2013.06.005] [PMID: 23791707]
[88]
Pettersson, M.; Johnson, D.S.; Subramanyam, C.; Bales, K.R. am Ende, C.W.; Fish, B.A.; Green, M.E.; Kauffman, G.W.; Mullins, P.B.; Navaratnam, T.; Sakya, S.M.; Stiff, C.M.; Tran, T.P.; Xie, L.; Zhang, L.; Pustilnik, L.R.; Vetelino, B.C.; Wood, K.M.; Pozdnyakov, N.; Verhoest, P.R.; O’Donnell, C.J. Design, synthesis, and pharmacological evaluation of a novel series of pyridopyrazine-1,6-dione γ-secretase modulators. J. Med. Chem., 2014, 57(3), 1046-1062.
[http://dx.doi.org/10.1021/jm401782h] [PMID: 24428186]
[89]
Bursavich, M.G.; Harrison, B.A.; Acharya, R.; Costa, D.E.; Freeman, E.A.; Hodgdon, H.E.; Hrdlicka, L.A.; Jin, H.; Kapadnis, S.; Moffit, J.S.; Murphy, D.A.; Nolan, S.; Patzke, H.; Tang, C.; Wen, M.; Koenig, G.; Blain, J.F.; Burnett, D.A. Design, Synthesis, and evaluation of a novel series of oxadiazine gamma secretase modulators for familial alzheimer’s disease. J. Med. Chem., 2017, 60(6), 2383-2400.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01620] [PMID: 28230986]
[90]
Tselepis, A.F.; Rizzo, M.; Goudevenos, I.A. Therapeutic modulation of lipoprotein-associated phospholipase A2 (Lp-PLA2). Curr. Pharm. Des., 2011, 17(33), 3656-3661.
[http://dx.doi.org/10.2174/138161211798220936] [PMID: 22074435]
[91]
Vittos, O.; Toana, B.; Vittos, A.; Moldoveanu, E. Lipoprotein-associated phospholipase A2 (Lp-PLA2): a review of its role and significance as a cardiovascular biomarker. Biomarkers, 2012, 17(4), 289-302.
[http://dx.doi.org/10.3109/1354750X.2012.664170] [PMID: 22401038]
[92]
Chen, X.; Xu, W.; Wang, K.; Mo, M.; Zhang, W.; Du, L.; Yuan, X.; Xu, Y.; Wang, Y.; Shen, J. Discovery of a novel series of imidazo[1,2-a]pyrimidine derivatives as potent and orally bioavailable lipoprotein-associated phospholipase A2 inhibitors. J. Med. Chem., 2015, 58(21), 8529-8541.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01024] [PMID: 26479945]
[93]
Skuza, G. Potential antidepressant activity of sigma ligands. Pol. J. Pharmacol., 2003, 55(6), 923-934.
[PMID: 14730086]
[94]
Wünsch, B. The σ(1) receptor antagonist S1RA is a promising candidate for the treatment of neurogenic pain. J. Med. Chem., 2012, 55(19), 8209-8210.
[http://dx.doi.org/10.1021/jm3011993] [PMID: 22951043]
[95]
Marrazzo, A.; Caraci, F.; Salinaro, E.T.; Su, T-P.; Copani, A.; Ronsisvalle, G. Neuroprotective effects of sigma-1 receptor agonists against beta-amyloid-induced toxicity. Neuroreport, 2005, 16(11), 1223-1226.
[http://dx.doi.org/10.1097/00001756-200508010-00018] [PMID: 16012353]
[96]
Schläger, T.; Schepmann, D.; Wünsch, B. Novel σ1 receptor ligands by oxa-pictet-spengler reaction of pyrazolylethanol. Synthesis, 2011, 2011(24), 3965-3974.
[http://dx.doi.org/10.1055/s-0031-1289607]
[97]
Schläger, T.; Schepmann, D.; Lehmkuhl, K.; Holenz, J.; Vela, J.M.; Buschmann, H.; Wünsch, B. Combination of two pharmacophoric systems: Synthesis and pharmacological evaluation of spirocyclic pyranopyrazoles with high σ1 receptor affinity. J. Med. Chem., 2011, 54(19), 6704-6713.
[http://dx.doi.org/10.1021/jm200585k] [PMID: 21859078]
[98]
Andrad, S.F.; Campos, E.F.; Teixeira, C.S.; Bandeira, C.C.; Lavorato, S.N.; Romeiro, N.C.; Bertollo, C.M.; Oliveira, M.C.; Souza-Fagundes, E.M.; Alves, R.J. Synthesis of novel 2,3,4-trisubstituted-oxazolidine derivatives and in vitro cytotoxic evaluation. Med. Chem., 2014, 10(6), 609-618.
[http://dx.doi.org/10.2174/15734064113096660057] [PMID: 24151866]
[99]
Andrade, S.F.; Teixeira, C.S.; Ramos, J.P.; Lopes, M.S.; Padua, R.M.; Oliveira, M.C.; Souza-Fagundes, E.M.; Alves, R.J. Synthesis of a novel series of 2,3,4-trisubstituted oxazolidines designed by isosteric replacement or rigidification of the structure and cytotoxic evaluation. MedChemComm, 2014, 5(11), 1693-1699.
[http://dx.doi.org/10.1039/C4MD00136B]
[100]
Tomasic, T.; Nabergoj, D.; Vrbek, S.; Zidar, N.; Jakopin, Z.; Zula, A.; Hodnik, Z.; Jukic, M.; Anderluh, M.; Ilas, J.; Dolenc, M.S.; Peluso, J.; Ubeaud-Sequier, G.; Muller, C.D.; Masic, L.P.; Kikelj, D. Analogues of the marine alkaloids oroidin, clathrodin, and hymenidin induce apoptosis in human HepG2 and THP-1 cancer cells. MedChemComm, 2015, 6(1), 105-110.
[http://dx.doi.org/10.1039/C4MD00286E]
[101]
Miao, B.; Skidan, I.; Yang, J.; Lugovskoy, A.; Reibarkh, M.; Long, K.; Brazell, T.; Durugkar, K.A.; Maki, J.; Ramana, C.V.; Schaffhausen, B.; Wagner, G.; Torchilin, V.; Yuan, J.; Degterev, A. Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains. Proc. Natl. Acad. Sci. USA, 2010, 107(46), 20126-20131.
[http://dx.doi.org/10.1073/pnas.1004522107] [PMID: 21041639]
[102]
Kommagalla, Y.; Cornea, S.; Riehle, R.; Torchilin, V.; Degterev, A.; Ramana, C.V. Optimization of the anti-cancer activity of phosphatidylinositol-3 kinase pathway inhibitor PITENIN-1: switching a thiourea with 1,2,3-triazole. MedChemComm, 2014, 5(9), 1359-1363.
[http://dx.doi.org/10.1039/C4MD00109E] [PMID: 25505943]
[103]
Jordan, M.A.; Wilson, L. Microtubules as a target for anticancer drugs. Nat. Rev. Cancer, 2004, 4(4), 253-265.
[http://dx.doi.org/10.1038/nrc1317] [PMID: 15057285]
[104]
Zhou, J.; Giannakakou, P. Targeting microtubules for cancer chemotherapy. Curr. Med. Chem. Anticancer Agents, 2005, 5(1), 65-71.
[http://dx.doi.org/10.2174/1568011053352569] [PMID: 15720262]
[105]
Pettit, G.R.; Singh, S.B.; Boyd, M.R.; Hamel, E.; Pettit, R.K.; Schmidt, J.M.; Hogan, F. Antineoplastic agents. 291. Isolation and synthesis of combretastatins A-4, A-5, and A-6(1a). J. Med. Chem., 1995, 38(10), 1666-1672.
[http://dx.doi.org/10.1021/jm00010a011] [PMID: 7752190]
[106]
Lu, Y.; Li, C.M.; Wang, Z.; Chen, J.; Mohler, M.L.; Li, W.; Dalton, J.T.; Miller, D.D. Design, synthesis, and SAR studies of 4-substituted methoxylbenzoyl-aryl-thiazoles analogues as potent and orally bioavailable anticancer agents. J. Med. Chem., 2011, 54(13), 4678-4693.
[http://dx.doi.org/10.1021/jm2003427] [PMID: 21557538]
[107]
Zhai, M.; Wang, L.; Liu, S.; Wang, L.; Yan, P.; Wang, J.; Zhang, J.; Guo, H.; Guan, Q.; Bao, K.; Wu, Y.; Zhang, W. Synthesis and biological evaluation of (1-aryl-1H-pyrazol-4-yl) (3,4,5-trimethoxyphenyl)methanone derivatives as tubulin inhibitors. Eur. J. Med. Chem., 2018, 156, 137-147.
[http://dx.doi.org/10.1016/j.ejmech.2018.05.058] [PMID: 30006160]
[108]
Zhai, M.; Liu, S.; Gao, M.; Wang, L.; Sun, J.; Du, J.; Guan, Q.; Bao, K.; Zuo, D.; Wu, Y.; Zhang, W. 3,5-Diaryl-1H-pyrazolo[3,4-b]pyridines as potent tubulin polymerization inhibitors: Rational design, synthesis and biological evaluation. Eur. J. Med. Chem., 2019, 168, 426-435.
[http://dx.doi.org/10.1016/j.ejmech.2018.12.053] [PMID: 30831410]
[109]
Pavana, R.K.; Shah, K.; Gentile, T.; Dybdal-Hargreaves, N.F.; Risinger, A.L.; Mooberry, S.L.; Hamel, E.; Gangjee, A. Sterically induced conformational restriction: Discovery and preclinical evaluation of novel pyrrolo[3,2-d]pyrimidines as microtubule targeting agents. Bioorg. Med. Chem., 2018, 26(20), 5470-5478.
[http://dx.doi.org/10.1016/j.bmc.2018.09.025] [PMID: 30297118]
[110]
Lee, T.; Christov, P.P.; Shaw, S.; Tarr, J.C.; Zhao, B.; Veerasamy, N.; Jeon, K.O.; Mills, J.J.; Bian, Z.; Sensintaffar, J.L.; Arnold, A.L.; Fogarty, S.A.; Perry, E.; Ramsey, H.E.; Cook, R.S.; Hollingshead, M.; Davis Millin, M.; Lee, K.M.; Koss, B.; Budhraja, A.; Opferman, J.T.; Kim, K.; Arteaga, C.L.; Moore, W.J.; Olejniczak, E.T.; Savona, M.R.; Fesik, S.W. Discovery of potent myeloid cell leukemia-1 (Mcl-1) inhibitors that demonstrate in vivo activity in mouse xenograft models of human cancer. J. Med. Chem., 2019, 62(8), 3971-3988.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01991] [PMID: 30929420]
[111]
Tafesse, F.G.; Ternes, P.; Holthuis, J.C. The multigenic sphingomyelin synthase family. J. Biol. Chem., 2006, 281(40), 29421-29425.
[http://dx.doi.org/10.1074/jbc.R600021200] [PMID: 16905542]
[112]
Chen, Y.; Cao, Y. The sphingomyelin synthase family: proteins, diseases, and inhibitors. Biol. Chem., 2017, 398(12), 1319-1325.
[http://dx.doi.org/10.1515/hsz-2017-0148] [PMID: 28742512]
[113]
Mo, M.; Yang, J.; Jiang, X.C.; Cao, Y.; Fei, J.; Chen, Y.; Qi, X.; Chu, Y.; Zhou, L.; Ye, D. Discovery of 4-Benzyloxybenzo[ d]isoxazole-3-amine derivatives as highly selective and orally efficacious human sphingomyelin synthase 2 inhibitors that reduce chronic inflammation in db/db mice. J. Med. Chem., 2018, 61(18), 8241-8254.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00727] [PMID: 30074791]


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