Potent s-cis-locked bithiazole correctors of ΔF508 cystic fibrosis transmembrane conductance regulator cellular processing for cystic fibrosis therapy

Journal of Medicinal Chemistry

Volumn 51, Issue 19, 2008, Pages 6044-6054

  Gui, Jun Yu ^a   Yoo, Choong L ^a   Yang, Baoxue ^b   Lodewyk, Michael W ^a   Meng, Liping ^a   El Idreesy, Tamer T ^a   Fettinger, James C ^a   Tantillo, Dean J ^a   Verkman, A S ^b   Kurth, Mark J ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLOHEPTANE DERIVATIVE; N [2 (5 CHLORO 2 METHOXYPHENYLAMINO) 5,6 DIHYDRO 4H CYCLOHEPTA[1,2 D:3,4 D']BITHIAZOL 2' YL]PIVALAMIDE; N [2 (5 CHLORO 2 METHOXYPHENYLAMINO) 7,8 DIHYDRO 6H CYCLOHEPTA[1,2 D:3,4 D']BITHIAZOL 2' YL]PIVALAMIDE; THIAZOLE DERIVATIVE; TRANSMEMBRANE CONDUCTANCE REGULATOR; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL BOND; CYSTIC FIBROSIS; DRUG CONFORMATION; DRUG DESIGN; DRUG POTENCY; DRUG SCREENING; DRUG SYNTHESIS; IC 50; MOLECULAR MODEL; STEREOSPECIFICITY; STRUCTURE ACTIVITY RELATION;

CYSTIC FIBROSIS; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; EPITHELIAL CELLS; HUMANS; MODELS, CHEMICAL; MOLECULAR STRUCTURE; PROTEIN PROCESSING, POST-TRANSLATIONAL; STEREOISOMERISM; THIAZOLES;

EID: 53549097399     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm800533c     Document Type: Article

References (52)

1. Bobadilla, J. L.; Macek, M; Fine, J. P.; Farrell, P. M. Cystic fibrosis: a worldwide analysis of CFTR mutations. Correlation with incidence data and application to screening. Hum. Mutat. 2002, 19, 575-606.
2. Pilewski, J. M.; Frizzell, R. A. Role of CFTR in airway disease. Physiol. Rev. 1999, 79, S215-S255.
3. Sheppard, D. N.; Welsh, M. J. Structure and function of the CFTR chloride channel. Physiol. Rev. 1999, 79, S23-S45.
4. (a) Denning, G. M.; Anderson, M. P.; Amara, J. F.; Marshall, J.; Smith, A. E.; Welsh, M. J. Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive. Nature 1992, 358, 761-764.
5. (b) Lukacs, G. L.; Mohamed, A.; Kartner, N.; Chang, X.-B.; Riordan, J. R.; Grinstein, S. Conformational maturation of CFTR but not its mutant counterpart (ΔF508) occurs in the endoplasmic reticulum and requires ATP. EMBO J. 1994, 13, 6076-6086.
6. (c) Kopito, R. R. Biosynthesis and degradation of CFTR. Physiol. Rev. 1999, 79, S167-S173.
7. (d) Du, K.; Sharma, M.; Lukacs, G. L. The ΔF508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of CFTR. Nat. Struct. Mol. Biol. 2005, 12, 17-25.
8. (a) Carlile, G. W.; Robert, R.; Zhang, D.; Teske, K. A.; Luo, Y.; Hanrahan, J. W.; Thomas, D. Y. Correctors of protein trafficking defects identified by a novel high-throughput screening assay. ChemBioChem 2007, 8, 1012-1020.
9. (b) Becq, F. On the discovery and development of CFTR chloride channel activators. Cur. Pharm. Des. 2006, 12, 471-484.
10. (c) Van Goor, F.; Straley, K. S.; Cao, D.; Gonzalez, J.; Hadida, S.; Hazlewood, A.; Joubran, J.; Knapp, T.; Makings, L. R; Miller, M.; Neuberger, T.; Olson, E.; Panchenko, V.; Rader, J.; Singh, A.; Stack, J. H.; Tung, R.; Grootenhuis, P. D. J.; Negulescu, P. Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules. Am. J. Physiol. 2006, 290, L1117-L1130.
11. Yang, H.; Shelat, A. A.; Guy, R. K.; Gopinath, V. S.; Ma, T.; Du, K.; Lukacs, G. L.; Taddei, A.; Folli, C.; Pedemonte, N.; Galietta, L. J. V.; Verkman, A. S. Nanomolar affinity small molecule correctors of defective AF508-CFTR chloride channel gating. J. Biol. Chem. 2003, 278, 35079-35085.
12. (a) Galietta, L. J.; Haggie, P. M.; Verkman, A. S. Green fluorescent protein-based halide indicators with improved chloride and iodide affinities. FEBS Lett. 2001, 499, 220-224.
13. (b) Pedemonte, N.; Lukacs, G. L.; Du, K.; Caci, E.; Zegarra-Moran, O.; Galietta, L. J. V.; Verkman, A. S. Small-molecule correctors of defective ΔF508-CFTR cellular processing identified by high-throughput screening. J. Clin. Invest. 2005, 115, 2564-2571.
14. (a) Illek, B.; Fischer, H.; Santos, G. F.; Widdicombe, J. H.; Machen, T. E.; Reenstra, W. W. cAMP-independent activation of CFTR Cl channels by the tyrosine kinase inhibitor genistein. Am. J. Physiol. 1995, 268, C886-C893.
15. (b) Schmidt, A.; Hughes, L. K.; Cai, Z.; Mendes, F.; Li, H.; Sheppard, D. N.; Amaral, M. D. Prolonged treatment of cells with genistein modulates the expression and function of the cystic fibrosis transmembrane conductance regulator. Br. J. Pharmacol. 2008, 153, 1311-1323.
16. Hwang, T.-C.; Horie, M.; Nairn, A. C.; Gadsby, D. C. Role of GTP-binding proteins in the regulation of cardiac chloride conductance. J. Gen. Physiol. 1992, 99, 465-489.
17. Kikelj, D.; Urleb, U. Product class 17: thiazoles. Sci. Synth. 2002, 11, 627-833.
18. Yoo, C. L.; Yu, G. J.; Yang, B.; Robins, L. I.; Verkman, A. S.; Kurth, M. J. 4′-Methyl-4,5′-bithiazole-based correctors of defective ΔF508-CFTR cellular processing. Bioorg. Med. Chem. Lett. 2008, 18, 2610-2614.
19. (a) Ahmed, Z.; Langer, P. Synthesis of functionalized diaryl ethers by [3 + 3] cyclization of 1,3-bis(silyl enol ethers) with 2-aryloxy-3-(silyloxy)alk- 2-en-1-ones. Synlett 2006, 3361-3363.
20. (b) Hayakawa, M.; Kaizawa, H.; Kawaguchi, K.-I.; Ishikawa, N.; Koizumi, T.; Ohishi, T.; Yamano, M.; Okada, M.; Ohta, M.; Tsukamoto, S.-I.; Raynaud, F. I.; Waterfield, M. D.; Parker, P.; Workman, P. Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110a inhibitors. Bioorg. Med. Chem. 2007, 15, 403-412.
21. (c) El-Gazzar, A. B. A.; Hussein, H. A. R.; Aly, A. S. Synthesis and reactions of polynuclear heterocycles: azolothienopyrimidines and thienothiazolopyrimidines. Phosphorus, Sulfur Silicon Relat. Elem. 2006, 181, 2771-2784.
22. (d) McInnes, C.; Wang, S.; Anderson, S.; O'Boyle, J.; Jackson, W.; Kontopidis, G.; Meades, C.; Mezna, M.; Thomas, M.; Wood, G.; Lane, D. P.; Fischer, P. M. Structural determinants of CDK4 inhibition and design of selective ATP competitive inhibitors. Chem. Biol. 2004, 11, 525-534.
23. Prepared by analogy with methodology reported in the following: Boyer, C.; Finazzi, G.; Laurent, P.; Haas, A.; Blancou, H. Synthesis and photosynthetic inhibition activity of substituted 5-[bis(trifluoromethyl)methyl]-2- aminothiazoles. J. Fluorine Chem. 2006, 127, 1522-1527.
24. Sayed, S. M.; Raslan, M. A.; Khalil, M. A.; Dawood, K. M. Synthesis and reactivity of cyanomethyl 2-amino-4-methylthiazolyl ketone. A facile synthesis of novel pyrazolo[5,1-c]-1,2,4-triazine, 1,2,4-triazolo[5,1-c]-1, 2,4-triazine, 1,2,4-triazino[4,3-a]benzimidazole, pyridazin-6-imine and 6-oxopyridazinone derivatives. Heteroat. Chem. 1999, 10, 385-390.
25. Yoo, C. L.; Fettinger, J. C.; Kurth, M. J. Stannous chloride in alcohol: a one-pot conversion of 2-nitro-N-arylbenzamides to 2,3-dihydro-1 H-quinazoline-4-ones. J. Org. Chem. 2005, 70, 6941-6943.
26. See, for example, the following: (a) Angyan, J.; Poirier, R. A.; Kucsman, A.; Csizmadia, I. G. Bonding between nonbonded sulfur and oxygen atoms in selected organic molecules (a quantum chemical study). J. Am. Chem. Soc. 1987, 109, 2237-2245.
27. (b) Meyer, E.; Joussef, A. C.; Gallardo, H.; Bortoluzzi, A. J.; Longo, R. L. 1,5-Type nonbonded O⋯S and S⋯S interactions in (acylimino) and (thioacylimino)benzothiazoline systems. Crystal structures and theoretical calculations. Tetrahedron 2003, 59, 10187-10193.
28. (c) Iwaoka, M.; Takemoto, S.; Okada, M.; Tomoda, S. Weak nonbonded S⋯X (X = O, N, and S) interactions in proteins. Statistical and theoretical studies. Bull. Chem. Soc. Jpn. 2002, 75, 1611-1625.
29. (d) Pomerantz, M. Planar 2,2′-bithiophenes with 3,3′- and 3,3′-,4,4′-substituents. A computational study. Tetrahedron Lett. 2003, 44, 1563-1565.
30. (e) Rábai, J.; Kapovits, I.; Jalsovszky, I.; Argay, Gy.; Fülöp, V.; Kálmán, A.; Koritsánszky, T. Molecular structures of cyclic sulfilimines without and with intramolecular sulfur-oxygen interaction: an X-ray study. J. Mol. Struct. 1996, 382, 13-21.
31. (f) Kucsman, Á.; Kapovits, I.; Párkányi, L.; Kálmán, A. Conformation of diaryl sulphides with intramolecular sulphur(II)-oxygen interaction: an X-ray study of methyl 2-(4-nitrophenylthio) benzoate and 2-diazoacetyl-4′-nitrodiphenyl sulphide. J. Mol. Struct. 1986, 140, 141-150.
32. amide bond is approximately 9 kcal/mol. This likely reflects both the loss of the favorable S⋯O interaction and the addition of an unfavorable O⋯N interaction.
33. 3 steric interaction with a phenyl hydrogen (see Figure 2a). However, rotation of the phenylamine group to the alternative conformation (which can occur with a barrier of approximately 4-6 kcal/mol) results in a structure that is slightly higher in energy and slightly more twisted (see Computational Methods and Figures S3 and S4 in the Supporting Information).
34. Lipinski, C. A.; Blizniak, T. E.; Craig, R. H. An improved preparation and use of 2-bromoacetoacetaldehyde in a new synthesis of 2-substituted-4- acetylimidazoles. J. Org. Chem. 1984, 49, 566-570.
35. Matulenko, M. A.; Lee, C.-H.; Jiang, M.; Frey, R. R.; Cowart, M. D.; Bayburt, E. K.; DiDomenico, S.; Gfesser, G. A.; Gomtsyan, A.; Zheng, G. Z.; McKie, J. A.; Stewart, A. O.; Yu, H.; Kohlhaas, K. L.; Alexander, K. M.; McGaraughty, S.; Wismer, C. T.; Mikusa, J.; Marsh, K. C.; Snyder, R. D.; Diehl, M. S.; Kowaluk, E. A.; Jarvis, M. F.; Bhagwat, S. S. 5-(3-Bromophenyl)-7-(6- morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine: structure-activity relationships of 7-substituted heteroaryl analogs as non-nucleoside adenosine kinase inhibitors. Bioorg. Med. Chem. 2005, 13, 3705-3720.
36. Kochetkov, N. K.; Nifant'ev, E. E.; Molodtsov, N. V. Bromination of -oxo acetals. Zh. Obshch. Khim. 1959, 29, 23302337.
37. (a) Katritzky, A. R.; Laurenzo, K. S.; Relyea, D. I. The preparation and fungicidal activity of a series of thiazolyl- and isothiazolyldiaryl-carbinols. Can. J. Chem. 1988, 66, 1617-1624.
38. (b) Chen, Y. L.; Cherry, K.; Corman, M. L.; Ebbinghaus, C. F.; Gamlath, C. B.; Liston, D.; Martin, B.-A.; Oborski, C. E.; Sahagan, B. G. Thiazole-diamides as potent γ-secretase inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 5518-5522.
39. Van der Mey, M.; Bommele, K. M.; Boss, H.; Hatzelmann, A.; Van Slingerland, M.; Sterk, G. J.; Timmerman, H. Synthesis and structure-activity relationships of cis-tetrahydrophthalazinone/pyridazinone hybrids: a novel series of potent dual PDE3/PDE4 inhibitory agents. J. Med. Chem. 2003, 46, 2008-2016.
40. Kreutzberger, A.; Schimmelpfennig, H. Antiviral drugs. XVIII. 2-Aminothizaoles by cleavage of the S-S bond of disulfidodicarbamidine. Arch. Pharm. (Weinheim, Ger.) 1981, 314, 385-391.
41. Schiavi, B.; Ahond, A.; Al-Mourabit, A.; Pupat, C.; Chiaroni, A.; Gaspard, C.; Potier, P. Synthesis of 5-deazathiogirolines: analogs of a natural antitumor agent. Tetrahedron 2002, 58, 4201-4215.
42. (a) Ragan, J. A.; Makowski, T. W.; Am Ende, D. J.; Clifford, P. J.; Young, G. R.; Conrad, A. K.; Eisenbeis, S. A. A practical synthesis of 1,3-cycloheptanedione. Org. Process Res. Dev. 1998, 2, 379-381.
43. (b) Bhushan, V.; Chandrasekaran, S. A convenient synthesis of cycloheptane-1,3-dione. Synth. Commun. 1984, 14, 339-345.
44. Frisch, M. J.; et al. Gaussian 03, revision D.01; Gaussian, Inc.: Pittsburgh, PA, 2003 (full reference in Supporting Information).
45. (a) Becke, A. D. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 1993, 98, 5648-5652.
46. (b) Becke, A. D. A new mixing of Hartree-Fock and local-density- functional theories. J. Chem. Phys. 1993, 98, 1372-1377.
47. (c) Lee, C.; Yang, W.; Parr, R. G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B 1988, 37, 785-789.
48. (d) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields. J. Phys. Chem. 1994, 98, 11623-11627.
49. (a) Barone, V.; Cossi, M. J. Quantum calculation of molecular energy gradients in solution by a conductor solvent model. J. Phys. Chem. A 1998, 102, 1995-2001.
50. (b) Barone, B.; Cossi, M.; Tomasi, J. Geometry optimization of molecular structures in solution by the polarizable continuum model. J. Comput. Chem. 1998, 19, 404-417.
51. (c) Takano, Y.; Houk, K. N. Benchmarking the conductor-like polarizable continuum model (CPCM) for aqueous solvation free energies of neutral and ionic organic molecules. J. Chem. Theor. Comput. 2005, 1, 70-77.
52. Müller, N.; Falk, A.; Gsaller, G. Ball & Stick, Molecular Graphics Application for MacOS Computers, version 4.0a12; Johannes Kepler University: Linz, Austria, 2004.