Discovery of 2-arylbenzoxazoles as upregulators of utrophin production for the treatment of duchenne muscular dystrophy

Journal of Medicinal Chemistry

Volumn 54, Issue 9, 2011, Pages 3241-3250

  Chancellor, Daniel R ^a   Davies, Kay E ^b   De Moor, Olivier ^a   Dorgan, Colin R ^a   Johnson, Peter D ^a   Lambert, Adam G ^a   Lawrence, Daniel ^a   Lecci, Cristina ^a   Maillol, Carole ^a   Middleton, Penny J ^a   Nugent, Gary ^a   Poignant, Séverine D ^a   Potter, Allyson C ^b   Price, Paul D ^a   Pye, Richard J ^a   Storer, Richard ^a   Tinsley, Jonathon M ^a   Van Well, Renate ^a   Vickers, Richard ^a   Vile, Julia ^a   Wilkes, Fraser J ^a   Wilson, Francis X ^a   Wren, Stephen P ^a   Wynne, Graham M ^a   more..

^a SUMMIT PLC   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2 (3,4 DICHLOROPHENYL) 5 (ETHYLSULFONYL)BENZO[D]OXAZOLE; 2 (4 CHLOROPHENYL) 5 (ETHYLSULFONYL)BENZO[D]OXAZOLE; 2 (4 CHLOROPHENYL)BENZO[D]OXAZOL 5 AMINE; 2 PHENYLBENZO[D]OXAZOL 5 AMINE; 5 (ETHYLSULFONYL) 2 (NAPHTHALEN 2 YL)BENZO[D]OXAZOLE; BENZOXAZOLE DERIVATIVE; LUCIFERASE; N (2 PHENYLBENZO[D]OXAZOL 5 YL)ACETAMIDE; N [2 (4 CHLOROPHENYL)BENZO[D]OXAZOL 5 YL]ISOBUTYRAMIDE; UNCLASSIFIED DRUG; UTROPHIN;

ANIMAL CELL; ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; DRUG HALF LIFE; DRUG STRUCTURE; DRUG SYNTHESIS; DUCHENNE MUSCULAR DYSTROPHY; HUMAN; HUMAN CELL; LIVER MICROSOME; MALE; MAXIMUM PLASMA CONCENTRATION; MICROWAVE IRRADIATION; MOUSE; NONHUMAN; PROTEIN EXPRESSION; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; TIME TO MAXIMUM PLASMA CONCENTRATION; UPREGULATION;

ANIMALS; BENZOXAZOLES; CELL LINE; MICE; MUSCULAR DYSTROPHY, DUCHENNE; STRUCTURE-ACTIVITY RELATIONSHIP; UP-REGULATION; UTROPHIN;

EID: 79955856839     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm200135z     Document Type: Article

References (29)

1. Nowak, K. J.; Davies, K. E. Duchenne muscular dystrophy and dystrophin: Pathogenesis and opportunities for treatment EMBO Rep. 2004, 5 (9) 872-876 (Pubitemid 350011231)
2. Cossu, G.; Sampaolesi, M. New therapies for Duchenne muscular dystrophy: Challenges, prospects and clinical trials Trends Mol. Med. 2007, 13 (12) 520-526 (Pubitemid 350130348)
3. Monaco, A. P.; Neve, R. L.; Colletti-Feener, C.; Bertelson, C. J.; Kurnit, D. M.; Kunkel, L. M. Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene Nature 1986, 323, 646-650 (Pubitemid 16008561)
4. See Wagner, K. R. Approaching a new age in Duchenne muscular dystrophy treatment Neurotherapeutics 2008, 5 (4) 583-591 and references therein
5. Hirawat, S.; Welch, E. M.; Elfring, G. L.; Northcutt, V. J.; Paushkin, S.; Hwang, S.; Leonard, E. M.; Almstead, N. G.; Ju, W.; Peltz, S. W.; Miller, L. L. Safety, Tolerability, and Pharmacokinetics of PTC124, a Nonaminoglycoside Nonsense Mutation Suppressor, Following Single- and Multiple-Dose Administration to Healthy Male and Female Adult Volunteers J. Clin. Pharmacol. 2007, 47, 430-444 (Pubitemid 46465953)
6. Tinsley, J. M.; Davies, K. E. Utrophin: A potential replacement for dystrophin? Neuromuscul. Disorders 1993, 3 (5-6) 537-539 (Pubitemid 24050833)
7. Blake, D. J.; Tinsley, J. M.; Davies, K. E. Utrophin: A structural and functional comparison to dystrophin Brain Pathol. 1996, 6 (1) 37-47 (Pubitemid 26078653)
8. For a description of mdx mouse model see Tinsley, J.; Deconinck, N.; Fisher, R.; Kahn, D.; Phelps, S.; Gillis, J.-M.; Davies, K. Expression of full-length utrophin prevents muscular dystrophy in mdx mice Nature Med. 1998, 4 (12) 1441-1444 (Pubitemid 28553471)
9. Kleopa, K. A.; Drousiotou, A.; Mavrikiou, E.; Ormiston, A.; Kyriakides, T. Naturally occurring utrophin correlates with disease severity in Duchenne muscular dystrophy Hum. Mol. Genet. 2006, 15 (10) 1623-1628 and references therein (Pubitemid 43904828)
10. Wynne, G. M.; Wren, S. P.; Johnson, P. D.; Price, P. D.; De Moor, O.; Nugent, G.; Tinsley, J. M.; Storer, R.; Mulvaney, A.; Pye, R. J.; Dorgan, C. R. Treatment of Duchenne Muscular Dystrophy, WO 2007/091106, 2007.
11. Benzoxazoles have attracted attention from the drug discovery community as leads in a variety of diverse programs. For some recent examples, see Johnson, S. M.; Connelly, S.; Wilson, I. A.; Kelly, J. W. Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors J. Med. Chem. 2008, 51 (2) 260-270
12. Harikrishnan, L. S.; Kamau, M. G.; Herpin, T. F.; Morton, G. C.; Liu, Y.; Cooper, C. B.; Salvati, M. E.; Qiao, J. X.; Wang, T. C.; Adam, L. P.; Taylor, D. S.; Chen, A. Y. A.; Yin, X.; Seethala, R.; Peterson, T. L.; Nirschl, D. S.; Miller, A. V.; Weigelt, C. A.; Appiah, K. K.; OConnell, J. C.; Lawrence, R. M. 2-Arylbenzoxazoles as novel cholesteryl ester transfer protein inhibitors: Optimization via array synthesis Bioorg. Med. Chem. Lett. 2008, 18, 2640-2644 (Pubitemid 351503882)
13. Lin, L. S.; Lanza, T. J., Jr.; Castonguay, L. A.; Kamenecka, T.; McCauley, E.; Van Riper, G.; Egger, L. A.; Mumford, R. A.; Tong, X.; MacCoss, M.; Schmidt, J. A.; Hagmann, W. K. Bioisosteric replacement of anilide with benzoxazole: potent and orally bioavailable antagonists of VLA-4 Bioorg. Med. Chem. Lett. 2004, 14 (9) 2331-2334 (Pubitemid 38481415)
14. Smith, D. A.; van de Waterbeemd, H.; Walker, D. K. In Pharmacokinetics and Metabolism in Drug Design; Mannhold, R.; Kubinyi, H.; Timmerman, H., Eds.; Wiley-VCH: New York, 2001; Vol. 13.
15. Wynne, G. M.; De Moor, O.; Wren, S. P.; Lecci, C.; Van Well, R.; Johnson, P. D.; Storer, R.; Poignant, S. Treatment of Duchenne Muscular Dystrophy. WO 2009/021750, 2009.
16. Wynne, G. M.; Wren, S. P.; Johnson, P. D.; Price, P. D.; De Moor, O.; Nugent, G.; Dorgan, C. R.; Tinsley, J. M.; Storer, R.; Mulvaney, A.; Pye, R. J. Treatment of Duchenne Muscular Dystrophy. WO 2007/091107 for work on analogues of 3 plus unpublished results (Summit plc; manuscript in preparation).
17. Ueda, S.; Nagasawa, H. Copper-catalysed synthesis of benzoxazoles via a regioselective C-H functionalization/C-O bond formation under an air atmosphere J. Org. Chem. 2009, 74 (11) 4272-4277
18. Bonnamour, J.; Bolm, C. Iron-catalyzed intramolecular O -arylation: Synthesis of 2-aryl benzoxazoles Org. Lett. 2008, 10 (13) 2665-2667
19. DeLuca, M. R.; Kerwin, S. M. The para-toluenesulfonic acid-promoted synthesis of 2-substituted benzoxazoles and benzimidazoles from diacylated precursors Tetrahedron 1997, 53 (2) 457-464 (Pubitemid 26422992)
20. Junbiao Chang, J.; Zhao, K.; Pan, S. Synthesis of 2-arylbenzoxazoles via DDQ promoted oxidative cyclisation of phenolic Schiff bases - A solution-phase strategy for library synthesis Tetrahedron Lett. 2002, 43, 951-954 and references therein (Pubitemid 34119231)
21. See ref 11b for an example of the use of microwave-activated benzoxazole synthesis.
22. Thomsen, I.; Clausen, K.; Scheibye, S.; Lawesson, S.-O. Thiation with 2,4- bis (4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide: N-methylthiopyrrolidone. Organic Syntheses; Wiley & Sons: New York, 1990; Collect. Vol. 7, pp 372-374.
23. Xu, G.; Searle, L. L.; Hughes, T. V.; Beck, A. K.; Connolly, P. J.; Abad, M. C.; Neeper, M. P.; Struble, G. T.; Springer, B. A.; Emanuel, S. L.; Gruninger, R. H.; Pandey, N.; Adams, M.; Moreno-Mazza, S.; Fuentes-Pesquera, A. R.; Middleton, S. A.; Greenberger, L. M. Discovery of novel 4-amino-6- arylaminopyrimidine-5-carbaldehyde oximes as dual inhibitors of EGFR and ErbB-2 protein tyrosine kinases Bioorg. Med. Chem. Lett. 2008, 18 (12) 3495-3499 (Pubitemid 351790731)
24. Corresponding benzotriazole, indazole, and imidazopyridine analogues of 8 are to be discussed elsewhere; Wren, S. P. Unpublished results.
25. Auld, D. S.; Lovell, S.; Thorne, N.; Lea, W. A.; Maloney, D. J.; Shen, M.; Rai, G.; Battaile, K. P.; Thomas, C. J.; Simeonov, A.; Hanzlik, R. P.; Inglese, J. Characterization of chemical libraries for luciferase inhibitory activity J. Med. Chem. 2008, 51 (8) 2372-2386 (Pubitemid 351628499)
26. Auld, D. S.; Lovell, S.; Thorne, N.; Lea, W. A.; Maloney, D. J.; Shen, M.; Rai, G.; Battaile, K. P.; Thomas, C. J.; Simeonov, A.; Hanzlik, R. P.; Inglese, J. Molecular basis for the high-affinity binding and stabilisation of firefly luciferase by PTC124 Proc. Natl. Acad. Sci. 2010, 107 (11) 4878-4883
27. Tinsley, J. M.; Fairclough, R. J.; Storer, R.; Wilkes, F. J.; Potter, A. C.; Squire, S.; Powell, D.; Cozzoli, A.; Capogrosso, R. F.; Lambert, A. G.; Wilson, F. X.; Wren, S. P.; De Luca, A.; Davies, K. E. Details of the in vivo efficacy of 1 will be reported elsewhere: Daily treatment with SMTC1100, a novel small molecule utrophin upregulator, dramatically reduces the dystrophic symptoms in the mdx mouse. PLoS ONE 2011, in press.
28. Poon, E.; Howman, E. V.; Newey, S. E.; Davies, K. E. Association of syncoilin and desmin: Linking intermediate filament proteins to the dystrophin-associated protein complex J. Biol. Chem. 2002, 277 (5) 3433-3439 (Pubitemid 34953212)
29. T method Methods 2001, 25 (4) 402-408 (Pubitemid 34164012)