Synthesis and profiling of a diverse collection of azetidine-based scaffolds for the development of CNS-focused lead-like libraries

Journal of Organic Chemistry

Volumn 77, Issue 17, 2012, Pages 7187-7211

  Lowe, Jason T ^a,b   Lee, Maurice D ^a   Akella, Lakshmi B ^a,b   Davoine, Emeline ^a   Donckele, Etienne J ^a   Durak, Landon ^a   Duvall, Jeremy R ^a   Gerard, Baudouin ^a,b   Holson, Edward B ^a   Joliton, Adrien ^a   Kesavan, Sarathy ^a,b   Lemercier, Berenice C ^a   Liu, Haibo ^a   Marié, Jean Charles ^a   Mulrooney, Carol A ^a   Muncipinto, Giovanni ^a   Welzel O'Shea, Morgan ^a,b   Panko, Laura M ^a,b   Rowley, Ann ^a   Suh, Byung Chul ^a   Thomas, Meryl ^a   Wagner, Florence F ^a   Wei, Jingqiang ^a   Foley, Michael A ^a   Marcaurelle, Lisa A ^a,b   more..

^a BROAD INSTITUTE OF MIT AND HARVARD   (United States)

^b EISAI INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AZETIDINE RING; AZETIDINES; CENTRAL NERVOUS SYSTEMS; FUNCTIONALIZED; IN-VITRO; PHARMACOKINETIC PROPERTIES; RING SYSTEMS; SOLID PHASE SYNTHESIS;

SCAFFOLDS;

ORGANIC COMPOUNDS;

( 2 PROPYL 1,2,2A,3,4,8B HEXAHYDROAZETO[2,3 C]QUINOLIN 1 YL)METHANOL; ( 6 METHYL 9 PHENYL 1,6 DIAZABICYCLO[6.2.0] DECAN 10 YL)METHANOL; (1 (HYDROXYMETHYL) 2 PROPYL 1,2A, 3,8B TETRAHYDROAZETO[2,3 C]QUINOLIN 4(2H) YL)ETHANONE; (4 (AMINOMETHYL) 3 PHENYL 1 PROPYLAZETIDIN 2 YL)METHANOL; (4 (METHYL SULFONYL ) 2 PROPYL 1,2,2A,3,4,8B HEXAHYDROAZETO[2,3 C]QUINOLIN 1 YL)METHANOL; (7 PHENYL 6 PROPYL 3,6 DIAZABICYCLO[3.1.1]HEPTAN 3 YL) ETHANONE; (9 (4 BROMOPHENYL) 1,6 DIAZABICYCLO[6.2.0] DECAN 10 YL)METHANOL; (9 PHENYL 1,6 DIAZABICYCLO[6.2.0]DECAN 10 YL) METHANOL; 1 PROPYL 2 HYDROXYMETHYL 3 PHENYL 1,6 DIAZASPIRO [3.3]HEPTANE; 1 PROPYL 2 HYDROXYMETHYL 3 PHENYL 6 ACETYL 1,6 DIAZASPIRO[3.3]HEPTANE; 1 PROPYL 2 HYDROXYMETHYL 3 PHENYL 6 METHYL 1,6 DIAZASPIRO[3.3]HEPTANE; 2 (ALLYL 1 (4 BROMOPHENYL) 1,3 DIHYDROXYPROPAN 2 YL)AMINO)ACETONITRILE; 3 (4 FLUOROBENZYL) 7 PHENYL 6 PROPYL 3,6 DIAZABICYCLO [3.1.1]HEPTANE; 3 (METHYLSULFONYL) 7 PHENYL 6 PROPYL 3,6 DIAZABICYCLO [3.1.1]HEPTANE; 3,4 METHYLENEDIOXYMETHAMPHETAMINE; 4 ( ARBONITRILE) 3 PHENYL 1 PROPYLAZETIDINE 2 HYDROXYMETHYL; 7 PHENYL 6 PROPYL 3,6 DIAZABICYCLO[3.1.1]HEPTANE; 7 PHENYL 8 ((TRITYLOXY)METHYL) 1,4 DIAZABICYCLO [4.2.0]OCTAN 2 ONE; 8 (HYDROXYMETHYL) 4 (METHYLSULFONYL) 7 PHENYL 1,4 DIAZABICYCLO[4.2.0]OCTAN 2 ONE; 8 (HYDROXYMETHYL) 4 METHYL 7 PHENYL 1,4 DIAZABICYCLO[4.2.0]OCTAN 2 ONE; AZETIDINE; DESVENLAFAXINE; DOPAMINE; EPHEDRINE; GLYCOPROTEIN P; MOLECULAR SCAFFOLD; MORPHINE; SPIROCYCLIC AZETIDINE DERIVATIVE; SUMANIROLE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ARTICLE; BLOOD BRAIN BARRIER; CARBON NUCLEAR MAGNETIC RESONANCE; CENTRAL NERVOUS SYSTEM; CHEMICAL STRUCTURE; COMPUTER MODEL; DRUG PENETRATION; DRUG TARGETING; IN VITRO STUDY; MOLECULAR LIBRARY; PHYSICAL CHEMISTRY; PROTON NUCLEAR MAGNETIC RESONANCE; STEREOCHEMISTRY; SYNTHESIS; ULTRA PERFORMANCE LIQUID CHROMATOGRAPHY;

ANIMALS; AZETIDINES; CACO-2 CELLS; CELL MEMBRANE PERMEABILITY; CENTRAL NERVOUS SYSTEM; ENDOTHELIAL CELLS; HUMANS; MICE; MOLECULAR STRUCTURE; SMALL MOLECULE LIBRARIES; SOLUBILITY; SPIRO COMPOUNDS; STEREOISOMERISM;

EID: 84866103356     PISSN: 00223263     EISSN: 15206904     Source Type: Journal    
DOI: 10.1021/jo300974j     Document Type: Article

References (82)

1. Morton, D.; Leach, S.; Cordier, C.; Warriner, S.; Nelson, A. Angew. Chem., Int. Ed. 2009, 48, 104-109
2. Arya, P.; Joseph, R.; Gan, Z.; Rakic, B. Chem. Biol. 2005, 12, 163-180
3. Tan, D. S. Nat. Chem. Biol. 2005, 1, 74-84
4. Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46-58
5. Schreiber, S. L. Science 2000, 287, 1964-1969
6. Tepper, R. I.; Roubenoff, R. In Genomics and Personalized Medicine; Willard, H. F.; Ginsburg, G. S., Eds; Elsevier Inc.: Amsterdam, 2009; pp 335-342.
7. Payne, R. H.; Gwynn, M. N.; Holmes, D. J.; Pompliano, D. L. Nat. Rev. Drug Discovery 2007, 6, 29-40
8. Huryn, D. M.; Jeffrey L. Brodsky, J. L.; Brummond, K. M.; Chambers, P. G.; Eyer, B.; Ireland, A. W.; Kawasumi, M.; LaPorte, M. G.; Lloyd, K.; Manteau, B.; Nghiem, P.; Quade, B.; Seguin, S. P.; Wipf, P. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6757-6762
9. Cui, J.; Hao, J.; Ulanovskaya, O. A.; Dundas, J.; Liang, J.; Kozmin, S. A. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6763-6768
10. Marcaurelle, L. A.; Comer, E.; Dandapani, S.; Duvall, J. R.; Gerard, B.; Kesavan, S.; Lee, M. D., IV; Liu, H.; Lowe, J. T.; Marie, J.-C.; Mulrooney, C. A.; Pandya, B. A.; Rowley, A.; Ryba, T. D.; Suh, B.-C.; Wei, J.; Young, D. W.; Akella, L. B.; Ross, N. T.; Zhang, Y.-L.; Fass, D. M.; Reis, S. A.; Zhao, W.-Z.; Haggarty, S. J.; Palmer, M.; Foley, M. A. J. Am. Chem. Soc. 2010, 132, 16962-16976
11. Bauer, R. A.; DiBlasi, C. M.; Tan, D. S. Org. Lett. 2010, 12, 2084-2087
12. Diaz-Gavilan, M.; Galloway, W. R. J. D.; O'Connell, K. M. G.; Hogkingson, J. T.; Spring, D. R. Chem. Commun. 2010, 46, 776-778
13. Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7, 47-50
14. Boldi, A. M. Curr. Opin. Chem. Biol. 2004, 8, 281-286
15. Taylor, S. J.; Taylor, A. M.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 1681-1685
16. Lo, M. M. C.; Neumann, C. S.; Nagayama, S.; Perlstein, E. O.; Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 16077-16086
17. Hajduk, P. J. Nature 2011, 470, 42-43
18. Cooper, T. W. J.; Campbell, I. B.; Macdonald, S. J. F. Angew. Chem., Int. Ed. 2010, 49, 8082-8091
19. Shelat, A. A.; Guy, K. Curr. Opin. Chem. Biol. 2007, 11, 244-251
20. Akella, L. B.; Marcaurelle, L. A. ACS Comb. Sci. 2011, 13, 357-364
21. Pajouhesh, H.; Lenz, G. R. NeuroRx 2005, 2, 541-553
22. Alavijeh, M. S.; Chishty, M.; Qaiser, M. Z.; Palmer, A. M. NeuroRx 2005, 2, 554-571
23. Teague, S. J.; Davis, A. M.; Leeson, P. D.; Oprea, T. Angew. Chem., Int. Ed. 1999, 38, 3745-3747
24. von Nussbaum, F.; Brands, M.; Hinzen, B.; Weigand, S.; Habich, D. Angew. Chem., Int. Ed. 2006, 45, 5072-5129
25. Singh, G. S. Mini-Rev. Med. Chem. 2004, 4, 69-92
26. Singh, G. S. Mini-Rev. Med. Chem. 2004, 4, 93-109
27. Buynak, J. D. Curr. Med. Chem. 2004, 11, 1951-1964
28. Veinberg, G.; Vorona, M.; Shestakova, I.; Kanepe, I.; Lukevics, E. Curr. Med. Chem. 2003, 10, 1741-1757
29. Kidwai, M.; Sapra, P.; Bhushan, K. R. Curr. Med. Chem. 1999, 6, 195-215
30. Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108, 3988-4035
31. Couty, F.; Evano, G.; Prim, D. Mini-Rev. Org. Chem. 2004, 1, 133-148
32. Drouillat, B.; Couty, F.; Marrot, J. Synlett 2009, 5, 767-770
33. Sivaprakasham, M; Couty, F.; Evano, G.; Srinivas, B.; Sridhar, R.; Rao, K. R. ARKIVOC 2007, 71-93
34. Couty, F.; Evano, G.; Vargas-Sanchez, M.; Bouzas, G. J. Org. Chem. 2005, 70, 9028-9031
35. Couty, F.; Evano, G.; Rabasso, N. Tetrahedron: Asymmetry 2003, 14, 2407-2412
36. Couty, F.; Prim, D. Tetrahedron: Asymmetry 2002, 13, 2619-2624
37. Agami, C.; Couty, F.; Evano, G. Tetrahedron: Asymmetry 2002, 13, 297-302
38. Comer, E.; Liu, H.; Joliton, A.; Clabaut, A.; Johnson, C.; Akella, L. B.; Marcaurelle, L. A. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6751-6756
39. Wrona, I. E.; Lowe, J. T.; Turbyville, T. J.; Johnson, T. R.; Beignet, J.; Beutler, J. A.; Panek, J. S. J. Org. Chem. 2008, 74, 1897-1916
40. Curran, D. P.; Zhang, Q.; Richard, C.; Lu, H.; Gudipathi, V.; Wilcox, C. S. J. Am. Chem. Soc. 2006, 128, 9561-9573
41. Dandapani, S.; Jeske, M.; Curran, D. P. J. Org. Chem. 2005, 70, 9447-9462
42. Zhang, Q. S.; Lu, H. J.; Curran, D. P. J. Am. Chem. Soc. 2004, 126, 36-37
43. Nishii, Y.; Maruyama, N.; Wakasugi, K.; Tanabe, Y. Bioorg. Med. Chem. 2001, 9, 33-39
44. Comer, E.; Rohan, E.; Deng, L.; Porco, J. A., Jr. Org. Lett. 2007, 9, 2123-2126
45. Ryba, T. D.; Depew, K. M.; Marcaurelle, L. A. J. Comb. Chem. 2009, 11, 110-116
46. (1 R,2 R)-2-Amino-1-(4-bromophenyl)propane-1,3-diol was purchased from Acme Bioscience (http://www.acmeca.com/) and selectively allylated to provide 1a using a procedure adapted from ref 11a.
47. (1 R,2 S)-Allyl amino diol 1b was accessed through a modified literature procedure. See: Martí?n, R.; Moyano, A.; Pericàs, M. A.; Riera, A. Org. Lett. 2000, 2, 93-95
48. Murineddu, G.; Murruzzu, C.; Curzu, M. M.; Chelucci, G.; Gotti, C.; Gaimarri, A.; Legnani, L.; Toma, L.; Pinna, G. A. Bioorg. Med. Chem. Lett. 2008, 18, 6147-6150
49. Loriga, G.; Manca, I.; Murineddu, G.; Chelucci, G.; Villa, S.; Gessi, S.; Toma, L.; Cignarella, G.; Pinna, G. A. Bioorg. Med. Chem. 2006, 14, 676-691
50. Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62, 7507
51. Wuitschik, G.; Rogers-Evans, M.; Buckl, A.; Bernasconi, M.; Märki, M.; Godel, T.; Fischer, H.; Wagner, B.; Parrilla, I.; Schuler, F.; Schneider, J.; Alker, A.; Schweizer, W. B.; Müller, K.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 4512-4515
52. Burkhard, J. A.; Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49, 9052-9067
53. Wuitschik, G.; Carreira, E. M.; Wagner, B.; Fischer, H.; Parrilla, I.; Schuler, F.; Rogers-Evans, M.; Müller, K. J. Med. Chem. 2010, 53, 3227-3246
54. Guérot, C.; Tchitchanov, B. H.; Knust, H.; Carreira, E. M. Org. Lett. 2011, 13, 780-783
55. Burkhard, J. A.; Guérot, C.; Knust, H.; Evans, M. R.; Carreira, E. M. Org. Lett. 2010, 12, 1944-1947
56. Burkhard, J. A.; Wagner, B.; Fischer, H.; Schuler, F.; Muller, K.; Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49, 3524-3527
57. Burkhard, J. A.; Guérot, C.; Knust, H.; Carreira, E. M. Org. Lett. 2012, 14, 66-69
58. Xu, R.; Czarniecki, M.; de Man, J.; Pan, J.; Qiang, L.; Root, Y.; Ying, S.; Su, J.; Sun, X.; Zhang, Y.; Yu, T.; Zhang, Y.; Hu, T.; Chen, S.-H. Tetrahedron Lett. 2011, 52, 3266-3270
59. Meyers, M. J.; Muizebelt, I.; van Wiltenburg, J.; Brown, D. L.; Thorarensen, A. Org. Lett. 2009, 11, 3523-3525
60. Deguest, G.; Bischoff, L.; Fruit, C.; Marsais, F. Org. Lett. 2007, 9, 1165-1167
61. Drouillat, B.; Couty, F.; David, O.; Evano, G.; Marrot, J. Synlett 2008, 9, 1345-1348
62. Kubo, T.; Katoh, C.; Yamada, K.; Okano, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron 2008, 64, 11230-11236
63. Omar-Amrani, R.; Thomas, A.; Brenner, E.; Schneider, R.; Fort, Y. Org. Lett. 2003, 5, 2311-2314
64. Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793-796
65. Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581-584
66. Niu, J.; Guo, P.; Kang, J.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem. 2009, 74, 5075-5078
67. Kuwabe, S. I.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 12202-12206
68. Hitchcock, S. A.; Pennington, L. D. J. Med. Chem. 2006, 49, 7559-7583
69. In silico analysis was performed using Stardrop interactive software platform: http://www.optibrium.com/stardrop.php.
70. The CNS MPO score was recently developed by Pfizer to provide a means to predict the potential success of CNS candidates in a clinical setting. The algorithm aims to enable greater flexibility in the design stage by eliminating hard cutoffs with respect to properties which may be interpreted as a potential hazard in regards to the behavior of a compound in vivo for details. See: Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. ACS Chem. Neurosci. 2010, 1, 435-449
71. Medina-Franco, J. L.; Maggiora, G. M.; Giulianotti, M. A.; Pinilla, C.; Houghten, R. A. Chem. Biol. Drug Des. 2007, 70, 393-412
72. The MFS map was generated using Pipeline Pilot: Pipeline Pilot, SciTegic, Inc.: 10188 Telesis Court, Suite 100, San Diego, CA 92121, USA; http://www.scitegic.com/products-services/pipeline-pilot.htm.
73. Sugano, K.; Kansy, M.; Artursson, P.; Avdeef, A.; Bendels, S.; Di, L.; Ecker, G. F.; Faller, B.; Fischer, H.; Gerebtzoff, G.; Lennernaes, H.; Senner, F. Nat. Rev. Drug Discovery 2010, 9, 597-614
74. Smith, D. A.; Di, L.; Kerns, E. H. Nat. Rev. Drug Discovery 2010, 9, 929-939
75. Dagenais, C.; Avdeef, A.; Tsinman, O.; Dudley, A.; Beliveau, R. Eur. J. Pharm. Sci. 2009, 38, 121-137
76. Irvine, J. D.; Takahashi, L.; Lockhart, K.; Cheong, J.; Tolan, J. W.; Selick, H. E.; Grove., J. R. J. Pharm. Sci. 1999, 88, 28-33
77. Artursson, P. J. Pharm. Sci. 1990, 79, 476-482
78. Anderle, P.; Niederer, E.; Rubas, W.; Hilgendorf, C.; Spahn-Langguth, H.; Wunderli-Allenspach, H.; Merkle, H. P.; Langguth, P. J. Pharm. Sci. 1998, 87, 757-762
79. Dandapani, S.; Marcaurelle, L. A. Nat. Chem. Biol. 2010, 6, 861-863
80. Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752-6756
81. Nadin, A.; Hattotuwagama, C.; Churcher, I. Angew. Chem., Int. Ed. 2012, 51, 1114-1122
82. Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512-7515