Discovery of N -(2,4-Di- tert -butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, Ivacaftor), a potent and orally bioavailable CFTR potentiator

Journal of Medicinal Chemistry

Volumn 57, Issue 23, 2014, Pages 9776-9795

  Hadida, Sabine ^a   Van Goor, Fredrick ^a   Zhou, Jinglan ^a   Arumugam, Vijayalaksmi ^a   McCartney, Jason ^a   Hazlewood, Anna ^a   Decker, Caroline ^a   Negulescu, Paul ^a   Grootenhuis, Peter D J ^a  

^a VERTEX PHARMACEUTICALS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 METHYL 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXYLIC ACID DIBENZYLAMIDE; 1 TERT BUTYL 2,4 DIAMINOBENZENE; 1 TERT BUTYL 2,4 DINITROBENZENE; 2 (2 NITROVINYLAMINO)BENZOIC ACID; 2 BROMO 1 TERT BUTYL 4 NITROBENZENE; 2 TERT BUTYL 5 NITROBENZONITRILE; 3 AMINOQUINOLIN 4 OL; 3 NITROQUINOLIN 4 OL; 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXYLIC ACID (1 METHYL 1H INDOL 6 YL)AMIDE; 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXYLIC ACID (1H INDOL 5 YL)AMIDE; 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXYLIC ACID (1H INDOL 6 YL)AMIDE; 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXYLIC ACID (1H PYRROLO[2,3 B]PYRIDIN 6 YL)AMIDE; 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXYLIC ACID (2,3 DIHYDRO 1H INDOL 6 YL)AMIDE; 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXYLIC ACID DIBENZYLAMIDE; 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXYLIC ACID NAPHTHALEN 2 YLAMIDE; 4 OXO N (2 OXOINDOLIN 6 YL) 1,4 DIHYDROQUINOLINE 3 CARBOXAMIDE; AMIDE; IVACAFTOR; N (1H BENZO[D]IMIDAZOL 6 YL) 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXAMIDE; N (1H INDAZOL 6 YL) 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXAMIDE; N (2 ISOPROPYLPHENYL) 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXAMIDE; N (2,6 DIETHYLPHENYL) 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXAMIDE; N (4 ETHYLPHENYL) 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXAMIDE; N (4 HYDROXYQUINOLIN 3 YL) 1H INDOLE 6 CARBOXAMIDE; N [2 (CYANOMETHYL)PHENYL] 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXAMIDE; N(4 ISOPROPYLPHENYL) 4 OXO 1,4 DIHYDROQUINOLINE 3 CARBOXAMIDE; N,N DIBENZYL 4 HYDROXYNICOTINAMIDE; QUINOLINE 3 CARBOXYLIC ACID DIBENZYLAMIDE; QUINOLONE DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG; AMINOPHENOL DERIVATIVE; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; N-(2,4-DI-TERT-BUTYL-5-HYDROXYPHENYL)-4-OXO-1,4-DIHYDROQUINOLINE-3-CARBOXAMIDE;

3T3 CELL LINE; ALLOMETRY; ANIMAL CELL; ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; BEAGLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG CONFORMATION; DRUG HALF LIFE; DRUG POTENCY; DRUG SOLUBILITY; EC50; HUMAN; HYDROGEN BOND; IC50; LIVER CLEARANCE; MACACA FASCICULARIS; MALE; MAXIMUM PLASMA CONCENTRATION; MOLECULAR WEIGHT; MOUSE; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; ANIMAL; CHILD; CYSTIC FIBROSIS; DOG; GENETICS; METABOLISM; SPRAGUE DAWLEY RAT; SYNTHESIS;

AMINOPHENOLS; ANIMALS; CHILD; CYSTIC FIBROSIS; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; DOGS; HUMANS; MACACA FASCICULARIS; MALE; MICE; NIH 3T3 CELLS; QUINOLONES; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84918587553     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm5012808     Document Type: Article

References (48)

1. Cystic Fibrosis Foundation: http://www.cff.org/.
2. Welsh, M. J.; Smith, A. E. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis Cell 1993, 73, 1251-1254
3. Rowe, S. M.; Miller, S.; Sorscher, E. J. Cystic Fibrosis N. Engl. J. Med. 2005, 352, 1992-2001
4. OSullivan, B. P.; Freedman, S. D. Cystic fibrosis Lancet 2009, 373, 1891-1904
5. Boyle, M. P.; DeBoeck, K. A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect Lancet Respir. Med. 2013, 12, 158-163
6. Rowe, S. M.; Clancy, J. P. Advances in cystic fibrosis therapies Curr. Opin. Pediatr. 2006, 18, 604-613
7. Van Goor, F.; Hadida, S.; Grootenhuis, P. D. J. Pharmacological rescue of mutant CFTR function for the treatment of cystic fibrosis Top. Med. Chem. 2008, 3, 91-120
8. Hadida, S.; Van Goor, F.; Grootenhuis, P. D. J. CFTR modulators for the treatment of cystic fibrosis Annu. Rep. Med. Chem. 2010, 45, 157-173
9. Pedemonte, N.; Lukacs, G. L.; Du, K.; Caci, E.; Zegarra-Moran, O.; Galietta, L. J. V.; Verkman, A. S. Small-molecule correctors of defective DeltaF508-CFTR cellular processing identified by high-throughput screening J. Clin. Invest. 2005, 115, 2564-2571
10. Zhang, W.; Fujii, N.; Naren, A. P. Recent advance and new perspectives in targeting CFTR for therapy of cystic fibrosis and enterotoxin-induced secretory diarrheas Future Med. Chem. 2012, 4, 329-345
11. Merk, D.; Schubert-Zsilavecz Repairing mutated proteins-development of small molecules targeting defects in the cystic fibrosis transmembrane conductance regulator Expert Opin. Drug Discovery 2013, 8, 691-708
12. Van Goor, F.; Straley, K. S.; Cao, D.; Gonzalez, J.; Hadida, S.; Hazlewood, A.; Joubran, J.; Knapp, T.; Miller, M.; Neuberger, T.; Olson, E.; Panchenco, V.; Rader, J.; Singh, A.; Stack, J. H.; Tung, R.; Grootenhuis, P. D. J.; Negulescu, P. Rescue of ΔF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules Am. J. Physiol.: Lung Cell. Mol. Physiol. 2006, 290, L1117-L1130
13. Zegarra-Moran, O.; Monteverde, M.; Galietta, L. J. V.; Moran, O. functional analysis of mutations in the putative binding site for cystic fibrosis transmembrane conductance regulator potentiators: interaction between activation and inhibition J. Biol. Chem. 2007, 282, 9098-9104
14. Pedemonte, N.; Sonawane, N. D.; Taddei, A.; Hu, J.; Zegarra-Moran, O.; Suen, Y. T.; Robins, L. I.; Dicus, C. W.; Willenbring, D.; Nantz, M. H.; Kurth, M. J.; Galietta, L. J. V.; Verkman, A. S. Phenylglycine and sulfonamide correctors of defective ΔF508 and G551D cystic fibrosis transmembrane conductance regulator chloride-channel gating Mol. Pharmacol. 2005, 67, 1797-1807
15. Van Goor, F.; Hadida, S.; Grootenhuis, P. D. J.; Burton, B.; Cao, D.; Neuberger, T.; Turnbull, A.; Singh, A.; Joubran, J.; Hazlewood, A.; Zhou, J.; McCartney, J.; Arumugam, V.; Decker, C.; Yang, J.; Young, C.; Olson, E. R.; Wine, J.; Frizzell, R. A.; Ashlock, M.; Negulescu, P. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770 Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 18825-18830
16. Accurso, F. J.; Rowe, S. M.; Clancy, J. P.; Boyle, M. P.; Dunitz, J. M.; Durie, P. R.; Sagel, S. D.; Hornick, D. B.; Konstan, M. W.; Donalson, S. H.; Moss, R. B.; Pilewski, J. M.; Rubenstein, R. C.; Uluer, A. Z.; Aitken, M. L.; Freedman, S. D.; Lynn, M. R.; Mayer-Hamblett, N.; Dong, Q.; Zha, J.; Stone, A. J.; Olson, E. R.; Ordoñez, C. L.; Campbell, P. W.; Ashlock, M. A.; Ramsey, B. W. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation N. Engl. J. Med. 2010, 363, 1991-2003
17. Ramsey, B. W.; Davies, J.; McElvaney, N. G.; Tullis, E.; Bell, S. C.; Dřevnek, P.; Griese, M.; McKone, E. F.; Wainwright, C. E.; Konstan, M. W.; Moss, R.; Ratjen, F.; Sermet-Gaudelus, I.; Rowe, S. M.; Dong, Q.; Rodriguez, S.; Yen, K.; Ordoñez, C. L.; Elborn, J. S. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation N. Engl. J. Med. 2011, 365, 1663-1672
18. U.S. Food and Drug Administration: Drugs@FDA, FDA Approved Drug Products. http://www.accessdata.fda.gov/drugsatfda-docs/label/2014/203188s007lbl.pdf.
19. A binding assay at Ricerca Biosciences, see www.ricerca.com. Percent activity at 10 μM was also measured for compounds 36 (47%), 45 (52%), and 48 (18%).
20. Torsional potentials were evaluated using internally developed software that utilizes the Szybki Toolkit from OpenEye Scientific Software [OpenEye Scientific Software, Santa Fe, NM; http://www.eyesopen.com/products/applications/szybki.html ]. Potentials were evaluated by restraining the torsion angle in question at 5° increments and energy minimizing the remainder of the molecule using the MMFF force field as reported by the following
21. Halgren, T. A. Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94 J. Comput. Chem. 1996, 17, 490-519
22. Halgren, T. A. MMFF VI. MMFF94s option for energy minimization studies J. Comput. Chem. 1999, 20, 720-729
23. Patani, G. A.; LaVoie, E. J. Bioisosterism: a rational approach in drug design Chem. Rev. 1996, 96, 3147-3176
24. Asselin, A. A.; Humber, L. G.; Voith, K.; Metcalf, G. Drug design via pharmacophore identification. Dopaminergic activity of 3 H -benz[ e ]indol-8-amines and their mode of interaction with the dopamine receptor J. Med. Chem. 1986, 29, 648-654
25. Asselin, A. A.; Humber, L. G.; Crosilla, D.; Oshiro, G.; Wojdan, A.; Grimes, D.; Heaslip, R. J.; Rimele, T. J.; Shaw, C. Indole-phenol bioisosterism. Synthesis and antihypertensive activity of pyrrolo analog of labetalol J. Med. Chem. 1986, 29, 1009-1015
26. Yu, H.; Burton, B.; Huang, C.-J.; Worley, J.; Cao, D.; Johnson, J. P.; Urrutia, A.; Joubran, J.; Seepersaud, S.; Sussky, K.; Hoffman, B. J.; Van Goor, F. Ivacaftor potentiation of multiple CFTR channels with gating mutations J. Cystic Fibrosis 2012, 11, 237-245
27. Van Goor, F.; Yu, H.; Nurton, B.; Hoffman, B. J. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function J. Cystic Fibrosis 2014, 13, 29-36
28. Pellowska, M.; Merk, D.; Schubert-Zsilavecz, M. Advances in personalized medicine-medicinal chemistry and pharmacology of vemurafenib and ivacaftor Pharmazie 2013, 68, 484-491
29. Milla, C. E. Cystic fibrosis in the era of genomic medicine Curr. Opin. Pediatr. 2013, 25, 323-328
30. Rommens, J. M.; Iannuzzi, M. C.; Kerem, B.; Drumm, M. L.; Melmer, G.; Dean, M.; Rozmahel, R.; Cole, J. L.; Kennedy, D.; Hidaka, N.; Zsiga, M.; Buchwald, M.; Riordan, J. R.; Tsui, L.-C.; Collins, F. S. Identification of the cystic fibrosis gene: chromosome walking and jumping Science 1989, 245, 1059-1065
31. Koga, H.; Itoh, A.; Murayama, S.; Suzue, S.; Irikura, T. Structure-activity relationships of antibacterial 6,7- and 7,8-disubstituted 1-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids J. Med. Chem. 1980, 23, 1358-1363
32. Shah, K. J.; Coats, E. A. Design, synthesis, and correlation analysis of 7-substituted 4-hydroxyquinoline-3-carboxylic acids as inhibitors of cellular respiration J. Med. Chem. 1977, 20, 1001-1006
33. Davies, R. V.; Fraser, J.; Nichol, K. J. EP 206616A2, 1986.
34. Coppola, G. M.; Hardtmann, G. E. The chemistry of 2 H -3,1-benzoxazine-2,4(1 H)-dione (isatoic anhydride). 7. Reactions with anions of active methylenes to form quinolines J. Heterocycl. Chem. 1979, 16, 1605-1610
35. Reich, M. F.; Fabio, P. F.; Lee, V. J.; Kuck, N. A.; Testa, R. T. Pyrido[3,4- e ]-1,2,4-triazines and related heterocycles as potential antifungal agents J. Med. Chem. 1989, 32, 2474-2485
36. Murphy, J. T.; Ridd, J. H. The rearrangement of aromatic nitro compounds. Part I. The reactions of nitroanilines in aqueous sulphuric acid J. Chem. Soc., Perkin Trans 2 1987, 12, 1767-1772
37. Derbyshire, D. H.; Waters, W. A. 108. The Significance of bromine cation in aromatic substitution. Part II. Preparative applicability J. Chem. Soc. 1950, 573-577
38. Tschaen, D. M.; Desmond, R.; King, A. O.; Fortin, M. C.; Pipik, B.; King, S.; Verhoeven, T. R. An improved procedure for aromatic cyanation Synth. Commun. 1994, 24 (6) 887-890
39. Kovendi, A.; Kircz, M. Synthesis of halo-, amino-, sulfonyl-, and aminosulfonyl(nitro)(ethyl)benzenes Chem. Ber. 1964, 97, 1896-1901
40. Capon, D.; Claudon, M. M.; Cornubert, R.; Lemoine, H.; Vivant, G. Cyclane stereochemistry. XLI. 2,4-, 3,4-, and 3,5-Dimethylcyclohexanones Bull. Soc. Chim. Fr. 1958, 847-853
41. 18F]ACF (2-[(2-amino-4-chloro-5-fluorophenyl)thio]- N, N -dimethyl-benzenemethanamine) J. Med. Chem. 2002, 45, 4716-4723
42. Charpentier, B. O.; Bernardon, J.-M.; Eustache, J.; Millois, C.; Martin, B.; Michel, S.; Shroot, B. Synthesis, structure-affinity relationships, and biological activities of ligands binding to retinoic acid receptor subtypes J. Med. Chem. 1996, 38, 4993-5006
43. Hennequin, L. F.; Thomas, A. P.; Johnstone, C.; Stokes, E. S. E.; Ple, P. A.; Lohmann, J.-J. M.; Ogilvie, D. J.; Dukes, M.; Wedge, S. R.; Curwen, J. O.; Kendrew, J.; Lambert-van der Brempt, C. Design and structure-activity relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors J. Med. Chem. 1999, 42, 5369-5389
44. Su, D.; Duan, J.; Yu, A.; Chen, Q. Synthesis of functionalized long-chain perfluoroalkanes from methyl halodifluoroacetates: a process of difluorocarbene insertion into copper-carbon bonds J. Fluorine Chem. 1993, 65 (1-2) 11-14
45. Hansch, C.; Helmkamp, G. Catalytic synthesis of heterocycles. VI. Dehydrocyclization of o -alkylbenzenes to indoles J. Am. Chem. Soc. 1951, 73, 3080-3082
46. Barlett, P. D.; Wallbillich, G. E. H.; Wingrove, A. S.; Swenton, J. S.; Montgomery, L. K.; Kramer, B. D. Cycloaddition. V. 2-Alkylbutadienes and 1,1-dichloro-2,2-difluoroethylene. The effect of diene conformation on mode of cycloaddition J. Am. Chem. Soc. 1968, 90, 2049-2056
47. Carpenter, M. S.; Easter, W. M.; Wood, T. F. Nitro musks. Isomers, homologs, and analogs of musk ambrette J. Org. Chem. 1951, 16, 586-617
48. Galietta, L. J.; Lantero, S.; Gazzolo, A.; Sacco, O.; Romano, L.; Rossi, G. A.; Zegarra-Moran, O. An improved method to obtain highly differenciated monolayers of human bronchial epithelial cells In Vitro Cell. Dev. Biol.: Anim. 1998, 34, 478-481