Macrocyclic drugs and clinical candidates: What can medicinal chemists learn from their properties?

Journal of Medicinal Chemistry

Volumn 57, Issue 2, 2014, Pages 278-295

  Giordanetto, Fabrizio ^a,b   Kihlberg, Jan ^a,c  

^a ASTRAZENECA R AND D   (Sweden)

^b Taros Chemicals GmbH and Co KG   (Germany)

^c UPPSALA UNIVERSITY   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

ANSAMYCIN DERIVATIVE; CYCLOPEPTIDE; CYCLOSPORIN A; MACROCYCLIC COMPOUND; MACROLIDE;

ARTICLE; CLINICAL TRIAL (TOPIC); DRUG BIOAVAILABILITY; DRUG CLASSIFICATION; DRUG MARKETING; HUMAN; MOLECULAR WEIGHT; SURFACE PROPERTY;

CLINICAL TRIALS AS TOPIC; DATABASES, CHEMICAL; DRUG ADMINISTRATION ROUTES; DRUG DESIGN; DRUGS, INVESTIGATIONAL; HUMANS; LACTAMS, MACROCYCLIC; MACROCYCLIC COMPOUNDS; MACROLIDES; PEPTIDES, CYCLIC; PHARMACEUTICAL PREPARATIONS; PHARMACOKINETICS;

EID: 84892163643     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm400887j     Document Type: Article

References (86)

1. Surade, S.; Blundell, T. L. Structural biology and drug discovery of difficult targets: the limits of ligandability Chem. Biol. 2012, 19, 42-50
2. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings Adv. Drug Delivery Rev. 1997, 23, 3-25 (Pubitemid 27046991)
3. Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry Nat. Rev. Drug Discovery 2007, 11, 191-200
4. Hann, M. M.; Keseru, G. M. Finding the sweet spot: the role of nature and nurture in medicinal chemistry Nat. Rev. Drug Discovery 2012, 11, 355-365
5. Mallinson, J.; Collins, I. Macrocycles in new drug discovery Future Med. Chem. 2012, 4, 1409-1438
6. Driggers, E. M.; Hale, S. P.; Lee, J.; Terrett, N. F. The exploration of macrocycles for drug discovery-an underexploited structural class Nat. Rev. Drug Discovery 2008, 7, 608-624 (Pubitemid 351927725)
7. DeLorbe, J. E.; Clements, J. H.; Whiddon, B. B.; Martin, S. F. Thermodynamic and structural effects of macrocyclic constraints in protein-ligand interactions ACS Med. Chem. Lett. 2010, 1, 448-452
8. Bogdan, A. R.; Davies, N. L.; James, K. Comparison of diffusion coefficients for matched pairs of macrocyclic and linear molecules over a drug-like molecular weight range Org. Biomol. Chem. 2011, 9, 7727-7733
9. Marsault, E.; Peterson, M. L. Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macocycles in drug discovery J. Med. Chem. 2011, 54, 1961-2004
10. Schreiber, S. L. Molecular diversity by design Nature 2009, 457, 153-154
11. Terrett, N. F. Methods for the synthesis of macrocycle libraries for drug discovery Drug Discovery Today: Technol. 2010, 7, e97-e104
12. Obrecht, D.; Chevalier, E.; Moehle, K.; Robinson, J. A. β-Hairpin protein epitope mimetic technology in drug discovery Drug Discovery Today: Technol. 2011, 9, e63-e69
13. Kotz, J. Bringing macrocycles full circle. SciBX 2012, 5, DOI: 10.1038/scibx.2012.1176.
14. Scannell, J. W.; Blanckley, A.; Boldon, H.; Warrington, B. Diagnosing the decline in pharmaceutical R&D efficiency Nat. Rev. Drug Discovery 2012, 11, 191-200
15. Bunnage, M. E. Getting pharmaceutical R&D back on track Nat. Chem. Biol. 2011, 7, 335-339
16. Knox, C.; Law, V.; Jewison, T.; Liu, P.; Ly, S.; Frolkis, A.; Pon, A.; Banco, K.; Mak, C.; Neveu, V.; Djoumbou, Y.; Eisner, R.; Guo, A. C.; Wishart, D. S. DrugBank 3.0: a comprehensive resource for "omics" research on drugs Nucleic Acids Res. 2011, 39, D1035-D1041
17. Thomson Reuters Integrity. http://integrity.prous.com.
18. About GOSTAR. http://gostardb.com/gostar/doc/HyperlinkDownloadPDF.pdf (accessed in April, 2013).
19. Cumming, J. G.; Winter, J.; Poirrette, A. Better compounds faster: the development and exploitation of a desktop predictive chemistry toolkit Drug Discovery Today 2012, 17, 923-927
20. Adis. http://www.springer.com/adis/databases?SGWID=0-1749113-0-0-0.
21. Ptachcinski, R. J.; Burckart, G. J.; Venkataramanan, R. Cyclosporine Drug Intell. Clin. Pharm. 1985, 19, 90-100 (Pubitemid 15152783)
22. Fahr, A. Cyclosporin clinical pharmacokinetics Clin. Pharmacokinet. 1993, 24, 472-495 (Pubitemid 23160616)
23. Fricker, G.; Drewe, J.; Huwyler, J.; Gutmann, H.; Beglinger, C. Relevance of p-glycoprotein for the enteral absorption of cyclosporin A: in vitro-in vivo correlation Br. J. Pharmacol. 1996, 118, 1841-1847 (Pubitemid 26252682)
24. Fatouros, D. M.; Karpf, D. M.; Nielsen, F. S.; Mullertz, A. Clinical studies with oral lipid based formulations of poorly soluble compounds Ther. Clin. Risk Manage. 2007, 3, 591-604 (Pubitemid 47496964)
25. El Tayar, N.; Mark, A. E.; Vallat, P.; Brunne, R. M.; Testa, B.; van Gunsteren, W. F. Solvent-dependent conformation and hydrogen-bonding capacity of cyclosporin A: evidence from partition coefficients and molecular dynamics simulations J. Med. Chem. 1993, 36, 3757-3764 (Pubitemid 24006703)
26. Alex, A.; Millan, D. S.; Perez, M.; Wakenhut, F.; Whitlock, G. A. Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space Med. Chem. Commun. 2011, 2, 669-674
27. Knipp, G. T.; Vander Velde, G. D.; Siahaan, T. J.; Borchardt, R. T. The effect of β-turn structure on the passive diffusion of peptides across Caco-2 cell monolayers Pharm. Res. 1997, 14, 1332-1340 (Pubitemid 27481063)
28. Okumu, F. W.; Pauletti, G. M.; Vander Velde, G. D.; Siahaan, T. J.; Borchardt, R. T. Effect of restricted conformational flexibility on the permeation of model hexapeptides across Caco-2 cell monolayers Pharm. Res. 1997, 14, 169-175 (Pubitemid 27146359)
29. Rezai, T.; Bock, J. E.; Zhou, M. V.; Kalyanaraman, C.; Lokey, R. S.; Jacobsen, M. P. Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: successful in silico prediction of the relative permeabilities of cyclic peptides J. Am. Chem. Soc. 2006, 128, 14073-14080 (Pubitemid 44657500)
30. Guimaraes, C. R. W.; Mathiowetz, A. M.; Shalaeva, M.; Goetz, G.; Liras, S. Use of 3D properties to characterize beyond rule-of-5 property space for passive permeation J. Chem. Inf. Model. 2012, 52, 882-890
31. White, T. R.; Renzelman, C. M.; Rand, A. C.; Rezai, T.; McEwen, C. M.; Gelev, V. M.; Turner, R. A.; Linington, R. G.; Leung, S. S. F.; Kalgutkar, A. S.; Bauman, J. N.; Zhang, Y.; Liras, S.; Price, D. A.; Mathiowetz, A. M.; Jacobsen, M. P.; Lokey, R. S. On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds Nat. Chem. Biol. 2011, 7, 810-817
32. Beck, J. G.; Chatterjee, J.; Laufer, B.; Kiran, M. U.; Frank, A. O.; Neubauer, S.; Ovadia, O.; Greenberg, S.; Gilon, C.; Hoffman, A.; Kessler, H. Intestinal permeability of cyclic peptides: common key backbone motifs identified J. Am. Chem. Soc. 2012, 134, 12125-12133
33. Zhanel, G. G.; Dueck, M.; Hoban, D. J.; Vercaigne, L. M.; Embil, J. M.; Gin, A. S.; Karlowsky, J. A. Review of macrolides and ketolides. Focus on respiratory tract infections Drugs 2001, 61, 443-498 (Pubitemid 32368062)
34. Waring, M. J. Defining optimum lipophilicity and molecular weight ranges for drug candidates-molecular weight dependent lower logD limits based on permeability Bioorg. Med. Chem. Lett. 2009, 19, 2844-2851
35. Egan, W. J.; Merz, J., K. M.; Baldwin, J. J. Prediction of drug absorption using multivariate statistics J. Med. Chem. 2000, 43, 3867-3877
36. Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D. Molecular properties that influence the oral bioavailability of drug candidates J. Med. Chem. 2002, 45, 2615-2623 (Pubitemid 34595232)
37. Marchi, E.; Montecchi, L.; Venturini, A. P.; Mascellan, G.; Brufani, M.; Cellai, L. 4-Deoxypyrido[1′,2′:1,2]imidazo[5,4- c ]rifamycin SV derivatives. A new series of semisynthetic rifamycins with high antibacterial activity and low gastroenteric absorption J. Med. Chem. 1985, 28, 960-963 (Pubitemid 15012508)
38. Brufani, M.; Cellai, L.; Cerrini, S.; Fedeli, W.; Marchi, E.; Segre, A.; Vaciago, A. X-ray crystal structure of 4-deoxy-3′-bromopyrido[1′, 2′-1,2]imidazo[5,4- c ]rifamycin SV J. Antibiot. 1984, 37, 1623-1627 (Pubitemid 15187747)
39. Pirsch, J. D.; Miller, J.; Deierhoi, M. H.; Vincenti, F.; Filo, R. S. A comparison of tacrolimus (Fk506) and cyclosporine for immunosuppression after cadaveric renal transplantation Transplantation 1997, 63, 977-983 (Pubitemid 27173021)
40. Tada, H.; Tsuchiya, N.; Satoh, S.; Kagaya, H.; Li, Z.; Sato, K.; Miura, M.; Suzuki, T.; Kato, T.; Habuchi, T. Impact of CYP3A5 and MDR1(ABCB1) C3435T polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients Transplant. Proc. 2005, 37, 1730-1732 (Pubitemid 40790812)
41. Gottlieb, A. B.; Griffiths, C. E. M.; Ho, V. C.; Lahfa, M.; Mrowietz, U.; Murrell, D. F.; Ortonne, J.-P.; Todd, G.; Cherill, R.; Marks, I.; Emady-Azar, S.; Paul, C. F. Oral pimecrolimus in the treatment of moderate to severe chronic plaque-type psoriasis: a double-blind, multicentre, randomized, dose-finding trial Br. J. Dermatol. 2005, 152, 1219-1227 (Pubitemid 40933421)
42. Kirsner, R. S.; Heffernan, M. P.; Antaya, R. Safety and efficacy of tacrolimus ointment versus pimecrolimus cream in the treatment of patients with atopic dermatitis previously treated with corticosteroids Acta Derm.-Venereol. 2010, 90, 58-64
43. Ashcroft, D. M.; Dimmock, P.; Garside, R.; Stein, K.; Williams, H. C. Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomised controlled trials Br. Med. J. 2005, 330, 516-522 (Pubitemid 40343354)
44. Billich, A.; Aschauer, H.; Aszódi, A.; Stuetz, A. Percutaneous absorption of drugs used in atopic eczema: pimecrolimus permeates less through skin than corticosteroids and tacrolimus Int. J. Pharm. 2004, 269, 29-35 (Pubitemid 38032821)
45. Weiss, H. M.; Fresneau, M.; Moenius, T.; Stuetz, A.; Billich, A. Binding of pimecrolimus and tacrolimus to skin and plasma proteins: implications for systemic exposure after topical application Drug Metab. Dispos. 2008, 36, 1812-1818
46. Mahalati, K.; Kaha, B. D. Clinical pharmacokinetics of sirolimus Clin. Pharmacokinet. 2001, 40, 573-585 (Pubitemid 32758580)
47. Hudes, G. R. Targeting mTOR in renal cell carcinoma Cancer 2009, 115, 2313-2320
48. Buckner, J. C.; Forouzesh, B.; Erlichman, C.; Hidalgo, M.; Boni, J. P.; Dukart, G.; Berkenblit, A.; Rowinsky, E. K. Phase I, pharmacokinetic study of temsirolimus administered orally to patients with advanced cancer Invest. New Drugs 2010, 28, 334-342
49. Burke, S. E.; Kuntz, R. E.; Schwartz, L. B. Zotarolimus (ABT-578) eluting stents Adv. Drug Delivery Rev. 2006, 58, 437-446 (Pubitemid 43833332)
50. Kirchner, G. I.; Meier-Wiedenbach, I.; Manns, M. P. Clinical pharmacokinetics of everolimus Clin. Pharmacokinet. 2004, 43, 83-95 (Pubitemid 38283132)
51. Canga, A. G.; Prieto, A. M. S.; Liebana, M. J. D.; Martinez, N. F.; Vega, M. S.; Vieitez, J. J. G. The pharmacokinetics and interactions of ivermectin in humans-a mini-review AAPS J. 2008, 10, 42-46
52. Edwards, G.; Dingsdale, A.; Helsby, N.; Orme, M. L.; Breckenridge, A. The relative systemic availability of ivermectin after administration as capsule, tablet, and oral solution Eur. J. Clin. Pharmacol. 1988, 35, 681-684 (Pubitemid 19000290)
53. Hoveyda, H. R.; Marsault, E.; Gagnon, R.; Mathieu, A. P.; Vézina, M.; Landry, A.; Wang, Z.; Benakli, K.; Beaubien, S.; Saint-Louis, C.; Brassard, M.; Pinault, J.-F.; Ouellet, L.; Bhat, S.; Ramaseshan, M.; Peng, X.; Foucher, L.; Beauchemin, S.; Bhérer, P.; Veber, D. F.; Peterson, M. L.; Fraser, G. L. Optimization of the potency and pharmacokinetic properties of macrocyclic ghrelin receptor agonist (part I): development of ulimorelin (TZP-101) from hit to clinic J. Med. Chem. 2011, 54, 8305-8320
54. Hosoe, K.; Mae, T.; Konishi, E.; Fujii, K.; Yamashita, K.; Yamane, T.; Hidaka, T.; Ohashi, T. Pharmacokinetics of KRM-1648, a new benzoxazinorifamycin, in rats and dogs Antimicrob. Agents Chemother. 1996, 40, 2749-2755 (Pubitemid 26404337)
55. Chen, Y.-X.; Caban, B.; Robertson, L. Escalating single-dose safety and pharmacokinetics of rifalazil in healthy volunteers AAPS J. 2004, 6, M1103
56. Chen, Y.-X.; Cabana, B.; Kivel, N.; Michaelis, A. Effect of food on the pharmacokinetics of rifalazil, a novel antibacterial, in healthy male volunteers J. Clin. Pharmacol. 2007, 47, 841-849
57. Mita, M. M.; Mita, A. C.; Chu, Q. S.; Rowinsky, E. K.; Fetterly, G. J.; Goldston, M.; Patnaik, A.; Mathews, L.; Ricart, A. D.; Mays, T.; Knowles, H.; Rivera, V. M.; Kreisberg, J.; Bedrosian, C. L.; Tolcher, A. W. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies J. Clin. Oncol. 2008, 26, 361-367 (Pubitemid 351171685)
58. Fetterly, G. J.; Mita, M. M.; Britten, C. D.; Poplin, E.; Tap, W. D.; Carmona, A.; Yonemoto, L.; Bedrosian, C. L.; Rubin, E. H.; Tolcher, A. W. Pharmacokinetics of oral deforolimus (AP23573, MK-8669) J. Clin. Oncol. 2008, 26 (15S) 14555
59. Still, J. G.; Schranz, J.; Degenhardt, T. P.; Scott, D.; Fernandes, P.; Gutierrez, M. J.; Clark, K. Pharmacokinetics of solithromycin (CEM-101) after single or multiple oral doses and effects of food on single-dose bioavailability in healthy adult subjects Antimicrob. Agents Chemother. 2011, 55, 1997-2003
60. Ross, D. B. The FDA and the case of Ketek N. Engl. J. Med. 2007, 356, 1601-1604 (Pubitemid 46631668)
61. Hopkins, S.; Scorneaux, B.; Huang, Z.; Murray, M. G.; Wring, S.; Smitley, C.; Harris, R.; Erdmann, F.; Fischer, G.; Ribeill, Y. SCY-635, a novel nonimmunosuppressive analog of cyclosporine that exhibits potent inhibition of hepatitis C virus RNA replication in vitro Antimicrob. Agents Chemother. 2010, 54, 660-672
62. Hopkins, S.; DiMassimo, B.; Rusnak, P.; Heuman, D.; Lalezari, J.; Sluder, A.; Scorneaux, B.; Mosier, S.; Kowalczyk, P.; Ribeill, Y.; Baugh, J.; Gallay, P. The cyclophilin inhibitor SCY-635 suppresses viral replication and induces endogenous interferons in patients with chronic HCV genotype 1 infection J. Hepatol. 2012, 57, 47-54
63. Aspeslet, L.; Freitag, D.; Trepanier, D.; Abel, M.; Naicker, S.; Kneteman, N.; Foster, R.; Yatscoff, R. ISATX247: a novel calcineurin inhibitor Transplant. Proc. 2001, 33, 1048-1051
64. Wasel, N.; Gupta, A.; Tomi, Z.; Kunynetz, R.; Guenther, L.; Bourcier, M.; Yatscoff, R. W.; Mayo, P.; Freitag, D.; Foster, R. T. Pharmacokinetics and pharmacodynamics of ISA247 in a phase III randomized, multicenter, double-blind, placebo-controlled study J. Am. Acad. Dermatol. 2006, 54, P36
65. Politano, A. D.; Sawyer, R. G. NXL-103, a combination of flopristin and linopristin, for the potential treatment of bacterial infections including community-acquired pneumonia and MRSA Curr. Opin. Invest. Drugs 2010, 11, 225-236
66. Malcolm, B. A.; Liu, R.; Lahser, F.; Agrawal, S.; Belanger, B.; Butkiewicz, N.; Chase, R.; Gheyas, F.; Hart, A.; Hesk, D.; Ingravallo, P.; Jiang, C.; Kong, R.; Lu, J.; Pichardo, J.; Prongay, A.; Skelton, A.; Tong, X.; Venkatraman, S.; Xia, E.; Girijavallabhan, V.; Njoroge, F. G. SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells Antimicrob. Agents Chemother. 2006, 50, 1013-1020 (Pubitemid 43327807)
67. Perni, R. B.; Almquist, S. J.; Byrn, R. A.; Chandorkar, G.; Chaturvedi, P. R.; Courtney, L. F.; Decker, C. J.; Dinehart, K.; Gates, C. A.; Harbeson, S. L.; Heiser, A.; Kalkeri, G.; Kolaczkowski, E.; Lin, K.; Luong, Y. P.; Rao, B. G.; Taylor, W. P.; Thomson, J. A.; Tung, R. D.; Wei, Y.; Kwong, A. D.; Lin, C. Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease Antimicrob. Agents Chemother. 2006, 50, 899-909 (Pubitemid 43327793)
68. Lamarre, D.; Anderson, P. C.; Bailey, M.; Beaulieu, P.; Bolger, G.; Bonneau, P.; Boes, M.; Cameron, D. R.; Cartier, M.; Cordingley, M. G. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus Nature 2003, 426, 186-189 (Pubitemid 37442587)
69. Tsantrizos, Y. S.; Bolger, G.; Bonneau, P.; Cameron, D. R.; Goudreau, N.; Kukolj, G.; LaPlante, S. R.; Llinàs-Brunet, M.; Nar, H.; Lamarre, D. Macrocyclic inhibitors of the NS3 protease as potential therapeutic agents of hepatitis C virus infection Angew. Chem., Int. Ed. 2003, 42, 1356-1360 (Pubitemid 36459971)
70. Raboisson, P.; de Kock, H.; Rosenquist, Å.; M. Nilsson, M.; Salvador-Oden, L.; Lin, T.-I.; Roue, N.; Ivanov, V.; Wähling, H.; Wickström, K.; Hamelink, E.; Edlund, M.; Vrang, L.; Vendeville, S.; Van de Vreken, W.; McGowan, D.; Tahri, A.; Hu, L.; Boutton, C.; Lenz, O.; Delouvroy, F.; Pille, G.; Surleraux, D.; Wigerinck, P.; Samuelsson, B.; Simmen, K. Structure-activity relationship study on a novel series of cyclopentane- containing macrocyclic inhibitors of the hepatitis C virus NS3 protease leading to the discovery of TMC435350 Bioorg. Med. Chem. Lett. 2008, 18, 4853-4858
71. Lin, T. I.; Lenz, O.; Fanning, G.; Verbinnen, T.; Delouvroy, F.; Scholliers, A.; Vermeiren, K.; Rosenquist, A.; Edlund, M.; Samuelsson, B.; Vrang, L.; de Kock, H.; Wigerinck, P.; Raboisson, P.; Simmen, K. In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor Antimicrob. Agents Chemother. 2009, 53, 1377-1385
72. Bradford, W. Z.; Rubino, C.; Porter, S.; Forrest, A.; Blatt, L. M.; Patat, A. A phase 1 study of the safety, tolerability, and pharmacokinetics of single ascending oral doses of the NS3/4A protease inhibitor ITMN-191 in healthy subjects Hepatology 2008, 48, 1146A
73. Reddy, M. B.; Chen, Y.; Haznedar, J. O.; Fretland, J.; Blotner, S.; Smith, P.; Tran, J. Q. Impact of low-dose ritonavir on danoprevir pharmacokinetics: results of computer-based simulations and a clinical drug-drug interaction study Clin. Pharmacokinet. 2012, 51, 457-465
74. Liverton, N. J.; Holloway, M. K.; McCauley, J. A.; Rudd, M. T.; Butcher, J. W.; Carroll, S. S.; DiMuzio, J.; Fandozzi, C.; Gilbert, K. F.; Mao, S.-S.; McIntyre, C. J.; Nguyen, K. T.; Romano, J. J.; Stahlhut, M.; Wan, B.-L.; Olsen, D. B.; Vacca, J. P. Molecular modeling based approach to potent P2-P4 macrocyclic inhibitors of hepatitis C NS3/4a protease J. Am. Chem. Soc. 2008, 130, 4607-4609 (Pubitemid 351500096)
75. McCauley, J. A.; McIntyre, C. J.; Rudd, M. T.; Nguyen, K. T.; Romano, J. J.; Butcher, J. W.; Gilbert, K. F.; Bush, K. J.; Holloway, M. K.; Swestock, J.; Wan, B.-L.; Carroll, S. S.; DiMuzio, J. M.; Graham, D. J.; Ludmerer, S. W.; Mao, S.-S.; Stahlhut, M. W.; Fandozzi, C. M.; Trainor, N.; Olsen, D. B.; Vacca, J. P.; Liverton, N. J. Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor J. Med. Chem. 2010, 53, 2443-2463
76. Liverton, N. J.; Carroll, S. S.; DiMuzio, J. M.; Fandozzi, C.; Graham, D. J.; Hazuda, D. J.; Holloway, M. K.; Ludmerer, S. W.; McCauley, J. A.; McIntyre, C. J.; Olsen, D. B.; Rudd, M. T.; Stahlhut, M.; Vacca, J. P. MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4a protease Antimicrob. Agents Chemother. 2010, 54, 305-311
77. Summa, V.; Ludmerer, S. W.; McCauley, J. A.; Fandozzi, C.; Burlein, C.; Claudio, G.; Coleman, P. J.; DiMuzio, J. M.; Ferrara, M.; Di Filippo, M.; Gates, A. T.; Graham, D. J.; Harper, S.; Hazuda, D. J.; McHale, C.; Monteagudo, E.; Pucci, V.; Rowley, M.; Rudd, M. T.; Soriano, A.; Stahlhut, M. W.; Vacca, J. P.; Olsen, D. B.; Liverton, N. J.; Carroll, S. S. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants Antimicrob. Agents Chemother. 2012, 56, 4161-4167
78. Vendeville, S.; Lin, T. I.; Hu, L.; Tahri, A.; McGowan, D.; Cummings, M. D.; Amssoms, K.; Canard, M.; Last, S.; Van den Steen, I.; Devogelaere, B.; Rouan, M. C.; Vijgen, L.; Berke, J. M.; Dehertogh, P.; Fransen, E.; Cleiren, E.; van der Helm, L.; Fanning, G.; Van Emelen, K.; Nyanguile, O.; Simmen, K.; Raboisson, P. Finger loop inhibitors of the HCV NS5b polymerase. Part II. Optimization of tetracyclic indole-based macrocycle leading to the discovery of TMC647055 Bioorg. Med. Chem. Lett. 2012, 22, 4437-4443
79. Devogelaere, B.; Berke, J. M.; Vijgen, L.; Dehertogh, P.; Fransen, E.; Cleiren, E.; van der Helm, L.; Nyanguile, O.; Tahri, A.; Amssoms, K.; Lenz, O.; Cummings, M. D.; Clayton, R. F.; Vendeville, S.; Raboisson, P.; Simmen, K. A.; Fanning, G. C.; Lin, T. I. TMC647055, a potent nonnucleoside hepatitis C virus NS5B polymerase inhibitor with cross-genotypic coverage Antimicrob. Agents Chemother. 2012, 56, 4676-4684
80. William, A. D.; Lee, A. C.-H.; Blanchard, S.; Poulsen, A.; Teo, E. L.; Nagaraj, H.; Tan, E.; Chen, D.; Williams, M.; Sun, E. T.; Goh, K. C.; Ong, W. C.; Goh, S. K.; Hart, S.; Jayaraman, R.; Pasha, M. K.; Ethirajulu, K.; Wood, J. M.; Dymock, B. W. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14, 19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3, 5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma J. Med. Chem. 2011, 54, 4638-4658
81. Younes, A.; Romaguera, J.; Fanale, M.; McLaughlin, P.; Hagemeister, F.; Copeland, A.; Neelapu, S.; Kwak, L.; Shah, J.; de Castro Faria, S.; Hart, S.; Wood, J.; Jayaraman, R.; Ethirajulu, K.; Zhu, J. Phase I study of a novel oral Janus kinase 2 inhibitor, SB1518, in patients with relapsed lymphoma: evidence of clinical and biologic activity in multiple lymphoma subtypes J. Clin. Oncol. 2012, 30, 4161-4167
82. Madan, B.; Goh, K. C.; Hart, S.; William, A. D.; Jayaraman, R.; Ethirajulu, K.; Dymock, B. W.; Wood, J. M. SB1578, a novel inhibitor of JAK2, FLT3, and c-Fms for the treatment of rheumatoid arthritis J. Immunol. 2012, 189, 4123-4134
83. Poulsen, A.; William, A.; Blanchard, S.; Nagaraj, H.; Williams, M.; Wang, H.; Lee, A.; Sun, E.; Teo, E. L.; Tan, E.; Goh, K. C.; Dymock, B. Structure-based design of nitrogen-linked macrocyclic kinase inhibitors leading to the clinical candidate SB1317/TG02, a potent inhibitor of cyclin dependant kinases (CDKs), Janus kinase 2 (JAK2), and Fms-like tyrosine kinase-3 (FLT3) J Mol. Model. 2013, 19, 119-130
84. Pasha, M. K.; Jayaraman, R.; Reddy, V. P.; Yeo, P.; Goh, E.; Williams, A.; Goh, K. C.; Kantharaj, E. Preclinical metabolism and pharmacokinetics of SB1317 (TG02), a potent CDK/JAK2/FLT3 inhibitor Drug Metab. Lett. 2012, 6, 33-42
85. Konings, I. R. H. M.; de Jonge, M. J. A.; Burger, H.; van der Gaast, A.; van Beijsterveldt, L. E. C.; Winkler, H.; Verweij, J.; Yuan, Z.; Hellemans, P.; Eskens, F. A. L. M. Phase I and pharmacological study of the broad-spectrum tyrosine kinase inhibitor JNJ-26483327 in patients with advanced solid tumours Br. J. Cancer. 2010, 103, 987-992
86. Hughes, J. D.; Blagg, J.; Price, D. A.; Bailey, S.; DeCrescenzo, G. A.; Devraj, R. V.; Ellsworth, E.; Fobian, Y. M.; Gibbs, M. E.; Gilles, R. W.; Greene, N.; Huang, E.; Krieger-Burke, T.; Loesel, J.; Wager, T.; Whiteley, L.; Zhang, Y. Physiochemical drug properties associated with in vivo toxicological outcomes Bioorg. Med. Chem. Lett. 2008, 18, 4872-4875