1426
R. Tripathy et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1421–1426
3. (a) Buhot, M. C.; Martin, S.; Segu, L. Ann. Med. 2000, 32, 210; (b) Meneses, A.
Drug News Perspect. 2001, 14, 396; (c) Perez-Garcia, G.; Meneses, A. Behav. Brain
Res. 2008, 195, 17.
4. King, M. V.; Marsden, C. A.; Fone, K. C. Trends Pharmacol. Sci. 2008, 29, 482.
5. For reviews see: (a) Rossé, G.; Schaffhauser, H. Curr. Topics Med. Chem. 2010, 10,
207; (b) Ivachtchenko, A. V.; Ivanenkov, Y. A.; Tkachenko, S. E. Exper. Opin. Ther.
Patents 2010, 20, 1171; Also see: (c) Ivachtchenko, A. V.; Golovina, E. S.;
Kadieva, M. G.; Kysil, V. M.; Mitkin, O. D.; Tkachenko, S. E.; Okun, I. Bioorg.
Medchem. 2011, 19, 1482; (d) Reid, M.; Carlyle, I.; Caulfield, W. L.; Clarkson, T.
R.; Cusick, F.; Epemolu, O.; Gilfillan, R.; Goodwin, R.; Jaap, D.; O’Donnel, E. C.;
Presland, J.; Rankovic, Z.; Spinks, G.; Thomson, A. M.; Thomson, F.; Starin, J.;
Wishort, G. Bioorg. Medchem. Lett. 2010, 20, 3713; (e) Nirogi, R. V. S.;
Deshpande, A. D.; Kambhampati, R.; Badange, R. K.; Kota, L.; Daulatabad, A.
V.; Shinde, A. K.; Ahmad, I.; Kandikere, V.; Jayarajan, P.; Dubey, P. K. Bioorg. Med.
Chem. Lett. 2011, 21, 346; (f) Liu, K. G.; Lo, J. R.; Comery, T.; Zhang, G. M.; Zhang,
J. Y.; Kowal, D. M.; Smith, D. L.; Di, L.; Kerns, E. H.; Schechter, L. E.; Robichaud, A.
J. Bioorg. Medchem. Lett. 2009, 19, 1115; (g) Trani, G.; Baddeley, S. M.; Briggs, M.
A.; Chuang, T. T.; Deeks, N. J.; Johnson, C. N.; Khazaragi, A. A.; Mead, T. L.;
Medhurst, A. D.; Milner, P. H.; Quinn, L. P.; Ray, A. M.; Rivers, D. A.; Stean, T. L.;
Stemp, G.; Trail, B. K.; Witty, D. R. Bioorg. Medchem. Lett. 2008, 18, 5698; (h) Liu,
K. G.; Lo, J. R.; Comery, T.; Zhang, G. M.; Zhang, J. Y.; Kowal, D. M.; Smith, D. L.;
Di, L.; Kerns, E. H.; Schechter, L. E.; Robichaud, A. J. Bioorg. Medchem. Lett. 2009,
19, 3214; (i) Seong, C. M.; Park, W. K.; Park, C. M.; Kong, J. Y.; Park, N. S. Bioorg.
Medchem. Lett. 2008, 18, 738; (j) Ahmed, M.; Briggs, M. A.; Bromidge, S. M.;
Buck, T.; Campbell, L.; Deeks, N. J.; Garner, A.; Gorden, L.; Hamprecht, D. W.;
Holland, V.; Johnson, C. N.; Medhurst, A. D.; Mitchell, D. J.; Moss, S. F.; Powles,
J.; Seal, J. T.; Stean, T. O.; Stemp, G.; Thompson, M.; Trail, B.; Upton, N.;
Winborn, K.; Witty, D. R. Bioorg. Medchem. Lett. 2005, 15, 4867; (k) Fleuente, T.;
Martin-Fontecha, M.; Sallander, J.; Benhamu, B.; Camplillo, M.; Medina, R. A.;
Pellissier, L.; Claeysen, S.; Dumuis, A.; Pardo, L.; Lopez-Rodriguez, M. L. J. Med.
Chem. 2010, 53, 1357; (l) Hayder, S. N.; Yun, H.; Andrae, P. M.; Mattes, J.; Zhang,
J.; Kramer, J.; Smith, D. L.; Huselton, C.; Graf, R.; Aschmies, S.; Schechter, L. E.;
Comery, T. A.; Robichaud, A. J. J. Med. Chem. 2010, 53, 2521.
Figure 2. Results of rat social recognition test with compound 15k.
vehicle, suggesting the reduction in RID by 15k was relevant to an
enhancement of short-term/working memory.
In conclusion, a novel 7-arylsulfonyl-1,2,3,4-tetrahydro-ben-
zo[4,5]furo[2,3-c]pyridine scaffold (3) for 5-HT6 receptor antago-
nists was designed based on a reported phamacophore model.
We demonstrated that the saturation of the double bond of the tet-
rahydro-furopyridine ring of 3a enhanced metabolic stability of the
resulting compound 4a (7-phenylsulfonyl-1,2,3,4,4a,9a-hexahy-
dro-benzo[4,5]furo[2,3-c] pyridine-HCl salt) albeit with 30-fold
loss in potency and introduction of two chiral centers. In our at-
tempts to optimize this series (4a), we found that the 2 or 3 posi-
tion on the distal benzene ring are important for activity.
Separation of enantiomers and subsequent optimization and SAR
study with bis-substituted aryl-sulfones provided potent 5-HT6
antagonist with improved PK profiles in rat. A potent, selective
functional antagonist from this study, 15k showed good oral bio-
availability (F = 39%) with good brain penetration (B/P = 2.78) and
in vivo activity in rat social recognition test.
6. Neale, A. C.; Jenkins, H.; Amend, D.; Lesem, M. Neuropsychopharmacology 2005,
30, S54.
7. López-Rodróguez, M. L.; Bellinda Benhamú, B.; De la Fuente, T.; Sanz, A.; Pardo,
L.; Campillo, M. J. Med. Chem. 2005, 48, 4216.
8. Ivachtchenko, A. V.; Dmitriev, D. E.; Golovina, E. S.; Dubrovskaya, E. S.; Kadieva,
M. G.; Koryakova, A. G.; Kysil, V. M.; Mitkin, O. D.; Tkachenko, S. E.; Okun, I. M.;
Vorobiov, A. A. Bioorg. Med. Chem. Lett. 2010, 20, 2133.
9. (a) Unpublished results.; (b) The scope of the manuscript is limited to SAR on
the sulfone-benzene ring only. For a related work from Cephalon: Sundar, B. G.;
Bailey, T. R.; Dunn, D. D.; Bacon, E. A.; Salvino, J. M.; Morton, G. C.; Aimone, L.
D.; Huang, Z.; Mathiasen, J. R.; Dicamillo, A.; Huffman, M. J.; McKenna, B. A.;
Kopec, K.; Lu, L. D.; Brown, R.; Qian, J.; Angeles, T.; Connors, T.; Spais, C.;
Holskin, B.; Galinis, D.; Duzic, E.; Schaffhauser, H.; Rosse, G. C. Bioorg. Med.
Chem. Lett. (communicated).
10. (a) Morice, C.; Domostoj, M.; Briner, K.; Mann, A.; Suffert, J.; Wermuth, C.-G.
Tetrahedron. Lett. 2001, 42, 6499; (b) Bacon, E. R.; Bailey, T. R.; Dunn, D. D.;
Hostetler, G. A.; Mchugh, R. J.; Morton, G. C.; Rosse, G. C.; Salvino, J. M.; Sundar,
B. G.; Tripathy, R. WO 2011087712
Acknowledgements
11. (a) Kabalka, G. W.; Gooch, E. E. J. Org. Chem. 1981, 46, 2582; (b) Kabalka, G. W.;
Sastry, K. A. R.; Hsu, H. C.; Hylarides, D. M. J. Org. Chem. 1981, 46, 3113; (c)
Kabalka, G. W.; Akula, M. R.; Zhang J. Nucl. Med. Biol. 2002, 29, 841.
12. Absolute configurations of 5a and 5b have not been determined.
13. See Schaffhauser, H.; Mathiasen, J. R.; Dicamillo, A.; Huffman, M. J.; Lu, L. D.;
McKenna, B. A.; Qian, J.; Marino, M. J. Biochem. Pharmacol. 2009, 78, 1035.
14. Fernandez-Rodriguez, M. A.; Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
2180. A CuI mediated coupling was carried out inplace of Pd(OAc)2.
15. (a) Rane, A. M.; Miranda, E. I.; Soderquist, J. A. Tetrahedron Lett. 1994, 35, 3225;
(b) Miranda, E. I.; Diaz, M. J.; Rosado, I.; Soderquist, J. A. Tetrahedron Lett. 1994,
35, 3221; (c) Huang, Y.; Mahmood, K.; Simpson, N. R. J. Labelled Compd.
Radiopharm. 1998, 41, 9; (d) Arnould, J. C.; Didelot, M.; Cadilhac, C.; Pasquet, M.
J. Tetrahedron Lett. 1996, 37, 4523.
We thank Mr. Kurt Josef for his help with NMR experiments. We
also thank Mr. Mark Olsen for chiral separation of enantiomers and
Ms. Rebecca A. Brown for bio-analysis.
References and notes
1. (a) Cansino, S. Int. J. Psychophysiol. 2009, 71, 64; (b) Gazzaley, A.; Sheridan, M.
A.; Cooney, J. W.; D’Esposito, M. Neuropsychology 2007, 21, 532; (c) Germano,
C.; Kinsella, G. J. Neuropsychol. Rev. 2005, 15, 1; (d) Gold, C. A.; Budson, A. E.
Exper. Rev. Neurother. 2008, 8, 1879.
2. (a) Gerard, C.; Martres, M. P.; Lefevre, K.; Miquel, M. C.; Verge, D.; Lanfumey, L.;
Doucet, E.; Hamon, M. E.; Mestikawy, S. Brain Res. 1997, 746, 207; (b) Hamon,
M.; Doucet, E.; Lefevre, K.; Miquel, M. C.; Lanfumey, L.; Insausti, R.; Frechilla, D.;
Del, R. J.; Verge, D. Neuropsychopharmacology 1999, 21, 68S.
16. A 24 h time course was followed for the compound 15k due to slower oral
absorption at the usual 6 h data collection.