Generic placeholder image

Medicinal Chemistry

Author(s): Nara Liessi, Emanuela Pesce, Annalisa Salis, Gianluca Damonte, Bruno Tasso, Elena Cichero, Nicoletta Pedemonte and Enrico Millo*

DOI: 10.2174/1573406416666200306114300

DownloadDownload PDF Flyer Cite As
Synthesis and Structure-activity Relationship of Aminoarylthiazole Derivatives as Potential Potentiators of the Chloride Transport Defect in Cystic Fibrosis

Page: [646 - 657] Pages: 12

  • * (Excluding Mailing and Handling)

Abstract

Background: Cystic fibrosis (CF) is the autosomal recessive disorder most common in Caucasian populations. It is caused by mutations in the cystic fibrosis transmembrane regulator protein (CFTR). CFTR is predominantly expressed at the apical plasma membranes of the epithelial cells lining several organs, and functions as a cAMP-regulated chloride/bicarbonate channel. To address the underlying causes of cystic fibrosis, two biomolecular activities are required, namely correctors to increase CFTR levels at the cell surface, and potentiators to allow the effective opening of the CFTR channel.

Objective: In our previous data, we demonstrated that some aminoarylthiazoles (AATs) have peculiar activity acting as correctors and as potentiator-like molecules.

Curiously, a compound called 1 has been shown to be markedly active as a potentiator. Now, we have further modified its scaffold at different portions, for the identification of molecules with improved potency and effectiveness on mutant CFTR.

Methods: Starting from this active compound, we synthesized a small library trying to improve the activity as potentiators. To extrapolate the contribution of a particular structural portion to bioactivity, we selectively modified one portion at a time.

Results: Our study has provided a structure-activity relationship (SAR) on AATs and led to the identification of some compounds, with a particular ability to act as CFTR potentiators.

Conclusion: Two compounds 2 and 13 appear to be promising molecules and could be used for the future development of potentiators of the chloride transport defect in cystic fibrosis.

Keywords: Cystic fibrosis, CFTR, modulators, potentiators, aminoarylthiazole, thioureas.

Graphical Abstract

[1]
Bergeron, C.; Cantin, A.M. Cystic Fibrosis: Pathophysiology of Lung Disease. Semin. Respir. Crit. Care Med., 2019, 40(6), 715-726.
[http://dx.doi.org/10.1055/s-0039-1694021] [PMID: 31659725]
[2]
Martiniano, S.L.; Sagel, S.D.; Zemanick, E.T. Cystic fibrosis: a model system for precision medicine. Curr. Opin. Pediatr., 2016, 28(3), 312-317.
[http://dx.doi.org/10.1097/MOP.0000000000000351] [PMID: 27031658]
[3]
Veit, G.; Avramescu, R.G.; Chiang, A.N.; Houck, S.A.; Cai, Z.; Peters, K.W.; Hong, J.S.; Pollard, H.B.; Guggino, W.B.; Balch, W.E.; Skach, W.R.; Cutting, G.R.; Frizzell, R.A.; Sheppard, D.N.; Cyr, D.M.; Sorscher, E.J.; Brodsky, J.L.; Lukacs, G.L. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol. Biol. Cell, 2016, 27(3), 424-433.
[http://dx.doi.org/10.1091/mbc.e14-04-0935] [PMID: 26823392]
[4]
Liu, F.; Zhang, Z.; Csanády, L.; Gadsby, D.C.; Chen, J. Molecular Structure of the human CFTR ion channel. Cell, 2017, 169(1), 85-95.e8.
[http://dx.doi.org/10.1016/j.cell.2017.02.024] [PMID: 28340353]
[5]
Vergani, P.; Lockless, S.W.; Nairn, A.C.; Gadsby, D.C. CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains. Nature, 2005, 433(7028), 876-880.
[http://dx.doi.org/10.1038/nature03313] [PMID: 15729345]
[6]
Moran, O. Model of the cAMP activation of chloride transport by CFTR channel and the mechanism of potentiators. J. Theor. Biol., 2010, 262(1), 73-79.
[http://dx.doi.org/10.1016/j.jtbi.2009.08.032] [PMID: 19766125]
[7]
Cuyx, S.; De Boeck, K. Treating the Underlying Cystic Fibrosis Transmembrane Conductance Regulator Defect in Patients with Cystic Fibrosis. Semin. Respir. Crit. Care Med., 2019, 40(6), 762-774.
[http://dx.doi.org/10.1055/s-0039-1696664] [PMID: 31659727]
[8]
Bell, S.C.; De Boeck, K.; Amaral, M.D. New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls. Pharmacol. Ther., 2015, 145, 19-34.
[http://dx.doi.org/10.1016/j.pharmthera.2014.06.005] [PMID: 24932877]
[9]
Pesce, E.; Bellotti, M.; Liessi, N.; Guariento, S.; Damonte, G.; Cichero, E.; Galatini, A.; Salis, A.; Gianotti, A.; Pedemonte, N.; Zegarra-Moran, O.; Fossa, P.; Galietta, L.J.; Millo, E. Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis. Eur. J. Med. Chem., 2015, 99, 14-35.
[http://dx.doi.org/10.1016/j.ejmech.2015.05.030] [PMID: 26041577]
[10]
Moran, O.; Zegarra-Moran, O. A quantitative description of the activation and inhibition of CFTR by potentiators. Genistein. FEBS Lett., 2005, 579(18), 3979-3983.
[http://dx.doi.org/10.1016/j.febslet.2005.06.026] [PMID: 15996659]
[11]
Van Goor, F.; Hadida, S.; Grootenhuis, P.D.; 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.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. USA, 2009, 106(44), 18825-18830.
[http://dx.doi.org/10.1073/pnas.0904709106] [PMID: 19846789]
[12]
Liessi, N.; Cichero, E.; Pesce, E.; Arkel, M.; Salis, A.; Tomati, V.; Paccagnella, M.; Damonte, G.; Tasso, B.; Galietta, L.J.V.; Pedemonte, N.; Fossa, P.; Millo, E. Synthesis and biological evaluation of novel thiazole- VX-809 hybrid derivatives as F508del correctors by QSAR-based filtering tools. Eur. J. Med. Chem., 2018, 144, 179-200.
[http://dx.doi.org/10.1016/j.ejmech.2017.12.030] [PMID: 29272749]
[13]
Sarkis, G.Y.; Al-Azawe, S. Preparation and spectral characterization of substituted 2-aminothiazoles. J. Chem. Eng. Data, 1973, 18, 99-102.
[http://dx.doi.org/10.1021/je60056a029]
[14]
Taurins, A.; Blaga, A. Synthesis of pyridyl- and quinolyl-substituted 2- aminothiazoles. J. Heterocycl. Chem., 1970, 7, 1137-1141.
[http://dx.doi.org/10.1002/jhet.5570070521]
[15]
Rasmussen, C.R.; Villani, F.J., Jr; Weaner, L.E.; Reynolds, B.E.; Hood, A.R.; Hecker, L.R.; Nortey, S.O.; Hanslin, A.; Costanzo, M.J.; Powell, E.T.; Molinari, A.J. Improved procedures for the preparation of cycloalkyl-, and arylalkyl-, and arylthioureas. Synthesis, 1988, 6, 456-459.
[http://dx.doi.org/10.1055/s-1988-27605]
[16]
Guha, S.K.; Wu, B.; Kim, B.S.; Baik, W.; Koo, S. TMSOTf-Catalyzed α-bromination of carbonyl compounds by N-bromosuccinimide. Tetrahedron Lett., 2006, 47, 291-293.
[17]
Liang, J. The synthesis of 3-aryl-6-alkylpyridazines. J. Heterocycl. Chem., 1984, 21, 1297-1299.
[http://dx.doi.org/10.1002/jhet.5570210511]
[18]
Suh, J.; Yum, E.K.; Cheon, H.G.; Cho, Y.S. Synthesis and biological evaluation of N-aryl-4-aryl-1,3-thiazole-2-amine derivatives as direct 5-lipoxygenase inhibitors. Chem. Biol. Drug Des., 2012, 80(1), 89-98.
[http://dx.doi.org/10.1111/j.1747-0285.2012.01371.x] [PMID: 22404847]