Targeting neurodegenerative diseases: Drug discovery in a challenging arena
10.1351/pac-con-11-11-09
Crossref journal-article
Walter de Gruyter GmbH
Pure and Applied Chemistry (374)
Abstract

Neurodegenerative diseases represent one of the health care community’s truly unmet medical needs. They can be loosely classified into two categories, acute and chronic. One of the best known chronic neurodegenerative diseases, Alzheimer’s disease, represents a serious health care problem that may well exceed the limits of current fiscal and care giver resources. No disease-modifying therapeutic agents have been identified, and the few available symptomatic treatments possess limitations in their duration of action and side effects. Despite decades of drug discovery research and numerous clinical trials, no truly effective treatment for stroke, the most prevalent acute neurodegenerative disease, has been identified. This article summarizes two recent drug discovery projects, one targeting Alzheimer’s disease and the other targeting ischemic stroke. Both projects involved design, synthesis, and biological evaluation of a novel series of heterocyclic derivatives.

Bibliography

Abou-Gharbia, M., & Childers, W. (2012). Targeting neurodegenerative diseases: Drug discovery in a challenging arena. Pure and Applied Chemistry, 84(7), 1543–1556.

Authors 2
  1. Magid Abou-Gharbia (first)
  2. Wayne Childers (additional)
References 46 Referenced 5
  1. 10.1016/j.neuron.2011.06.031, S. Saxena, P. Caroni. Neuron71, 35 (2011). (10.1016/j.neuron.2011.06.031)
  2. 10.2165/11595870-000000000-00000, For a recent review, see: N. Herrmann, S. A. Chau, I. Kircanski, K. L. Lanctot. Drugs71, 2031 (2011). (10.2165/11595870-000000000-00000)
  3. 10.1007/s12264-008-0105-7, X.-P. Wang, H.-L. Ding. Neurosci. Bull.24, 105 (2008). (10.1007/s12264-008-0105-7)
  4. A. Wimo, M. Prince. World Alzheimer Report 2010, Alzheimer’s Disease International, available online at: <http://www.alz.co.uk/research/files/WorldAlzheimerReport2010.pdf>.
  5. G. M. Shanker, D. M. Walsh. Mol. Neurodegen. (2009). Available online at: <http://www.molecularneurodegeneration.com>.
  6. 10.1016/j.jalz.2007.11.008, For a recent review, see: A. D. Korczyn. Alzheimer’s Dementia4, 176 (2008).
  7. 10.1126/science.1197623, K. G. Mawuenyega, W. Sigurnson, V. Ovod, L. Munsell, T. Kasten, J. C. Morris, K. E. Yarasheski, R. J. Bateman. Science330, 1774 (2010). (10.1126/science.1197623)
  8. 10.1007/s11064-009-0054-1, N. Marks, M. J. Berg. Neurochem. Res.35, 181 (2010). (10.1007/s11064-009-0054-1)
  9. 10.1021/jm900188z, A. F. Kreft, R. Martone, A. Porte. J. Med. Chem.52, 6169 (2009). (10.1021/jm900188z)
  10. 10.2174/092986709788186174, W.-H. Huang, R. Sheng, Y.-A. Hu. Curr. Med. Chem.16, 1806 (2009). (10.2174/092986709788186174)
  11. B. P. Imbimbo, I. Peretto. Curr. Opin. Invest. Drugs10, 721 (2009).
  12. Eli Lilly Press Release, 17 August 2010, accessed on 14 October 2011 at: <http://newsroom.lilly.com/releasedetail.cfm?ReleaseID=499794>.
  13. 10.1021/jm801252w, S. C. Mayer, A. F. Kreft, B. Harrison, M. Abou-Gharbia, M. Antane, S. Aschmies, K. Atchison, M. Chlenov, D. C. Cole, T. Comery, G. Diamantidis, J. Ellingboe, K. Fan, R. Galante, C. Gonzales, D. M. Ho, M. E. Hoke, Y. Hu, D. Huryn, U. Jain, M. Jin, K. Kremer, D. Kubrak, M. Lin, P. Lu, R. Magolda, R. Martone, W. Moore, A. Oganesian, M. N. Pangalos, A. Porte, P. Reinhart, L. Resnick, D. R. Riddell, J. Sonnenberg-Reines, J. R. Stock, S.-C. Sun, E. Wagner, T. Wang, K. Woller, Z. Xu, M. M. Zaleska, J. Zeldis, M. Zhang, H. Zhou, J. S. Jacobsen. J. Med. Chem.51, 7348 (2008). (10.1021/jm801252w)
  14. 10.1016/j.bmcl.2009.08.072, A. Hall, R. L. Elliot, G. M. P. Giblin, I. Hussain, J. Musgrave, A. Naylor, R. Sasse, B. Smith. Bioorg. Med. Chem. Lett.20, 1306 (2010). (10.1016/j.bmcl.2009.08.072)
  15. 10.2174/092986709788186174, W.-H. Huang, R. Sheng, H.-A. Hu. Curr. Med. Chem.16, 1806 (2009). (10.2174/092986709788186174)
  16. 10.1021/jm9006752, M. S. Malamas, J. Erdei, I. Gunawan, K. Barnes, M. Johnson, Y. Hui, J. Turner, Y. Hu, E. Wagner, K. Fan, A. Olland, J. Bard, A. J. Robichaud. J. Med. Chem.52, 6314 (2009). (10.1021/jm9006752)
  17. 10.1006/abio.1994.1134, P. Wu, L. Brand. Anal. Biochem.218, 1 (1994).
  18. 10.1515/BC.2008.025, I. Schechter, E. Ziv. Biol. Chem.389, 313 (2008). (10.1515/BC.2008.025)
  19. 10.1021/jm901414e, M. S. Malamas, J. Erdei, I. Gunawan, J. Turner, Y. Hu, E. Wagner, K. Fan, R. Chopra, A. Olland, J. Bard, S. Jacobsen, R. L. Magolda, M. Pangalos, A. J. Robichaud. J. Med. Chem.53, 1146 (2010). (10.1021/jm901414e)
  20. 10.1126/science.274.5284.99, K. Hsiao, P. Chapman, S. Nilson, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, G. Cole. Science274, 99 (1996). (10.1126/science.274.5284.99)
  21. 10.1523/JNEUROSCI.2693-05.2005, T. A. Comery, R. L. Martone, S. Aschmies, K. P. Atchison, G. Diamantidis, X. Gong, H. Zhou, A. F. Kreft, M. N. Pangalos, J. Sonnenberg-Reines, J. S. Jacobsen, K. L. Marquis. J. Neurosci.25, 8898 (2005).
  22. World Health Organization. “STEPwise approach to stroke surveillance”, accessed online on 14 October 2011 at: <http://www.who.int/chp/steps/stroke/en/index.html>.
  23. 10.1161/STROKEAHA.107.181486, H. P. Adams Jr., G. del Zoppo, J. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, P. D. Lyden, L. B. Morgenstern, A. I. Qureshi, R. H. Rosenwasser, P. A. Scott, E. F. M. Wijdicks. Stroke38, 1655 (2007). (10.1161/STROKEAHA.107.181486)
  24. 10.1097/01.WCB.0000137868.50767.E8, J. Kaur, Z. Zhao, G. M. Kline, E. H. Lao, A. M. Buchan. J. Cereb. Blood Flow Metab.24, 945 (2004). (10.1097/01.WCB.0000137868.50767.E8)
  25. 10.1002/ana.20741, V. E. O’Collins, M. R. Macleod, G. A. Donnan, L. L. Horky, B. H. van der Worp, D. W. Howells. Ann. Neurol.59, 467 (2006). (10.1002/ana.20741)
  26. 10.1038/nrn2074, H. T. Ghashghaei, C. Lai, E. S. Anton. Nat. Rev. Neurosci.8, 141 (2007). (10.1038/nrn2074)
  27. 10.1186/1471-2377-11-75, A. M. Enciu, M. I. Nicolescu, C. G. Manole, D. F. Muresanu, L. M. Popescu, B. O. Popescu. BMC Neurol.11, 75 (2011). (10.1186/1471-2377-11-75)
  28. 10.1212/WNL.0b013e3181cfc1a5, G. Pyne-Geithman. Neurology74, 352 (2010). (10.1212/WNL.0b013e3181cfc1a5)
  29. 10.1016/j.neuropharm.2008.10.006, M. M. Zaleska, M. L. T. Mercado, J. Chavez, G. Z. Feuerstein, M. N. Pangalos, A. Wood. Neuropharmacology56, 329 (2009). (10.1016/j.neuropharm.2008.10.006)
  30. 10.7164/antibiotics.28.721, C. Vezina, A. Kudelski, S. N. Sehgal. J. Antibiot.28, 721 (1975). (10.7164/antibiotics.28.721)
  31. 10.1016/S0009-9120(98)00045-9, S. N. Sehgal. Clin. Biochem.31, 335 (1998). (10.1016/S0009-9120(98)00045-9)
  32. 10.1101/gad.1212704, N. Hay, N. Sonenberg. Genes Dev.18, 1926 (2004). (10.1101/gad.1212704)
  33. 10.1016/j.cell.2006.01.016, S. Wullschleger, R. Loewith, M. N. Hall. Cell124, 471 (2006). (10.1016/j.cell.2006.01.016)
  34. 10.1126/science.273.5272.239, J. Choi, J. Chen, S. L. Schreiber, J. Clardy. Science273, 239 (1996). (10.1126/science.273.5272.239)
  35. 10.1073/pnas.91.8.3191, W. E. Lyons, E. B. George, T. M. Dawson, J. P. Steiner, S. H. Snyder. Proc. Nat. Acad. Sci. USA94, 3191 (1994). (10.1073/pnas.91.8.3191)
  36. 10.1038/ja.2006.26, M. Y. Summers, M. Leighton, D. Liu, K. Pong, E. I. Graziani. J. Antibiot.59, 184 (2006). (10.1038/ja.2006.26)
  37. 10.1016/j.jneumeth.2007.03.018, D. Liu, B. McIlvain, M. Fennell, J. Dunlop, A. Wood, M. M. Zaleska, E. I. Graziani, K. Pong. J. Neurosci. Meth.163, 310 (2007). (10.1016/j.jneumeth.2007.03.018)
  38. E. Graziani. In RSC Drug Discovery Series, #4. Accounts in Drug Discovery: Case Studies in Medicinal Chemistry, J. C. Barrish, P. H. Carter, P. T. W. Cheng, R. Zohler (Eds.), pp. 316–330, RCS Publishing, London (2011).
  39. Neuronal survival was determined by measuring neurofilament content in cultured rat cortical neurons using an ELISA assay.
  40. 10.1006/bbrc.1993.1563, T. D. Ocain, K. Longhi, R. J. Steffan, R. G. Caccese, S. N. Sehgal. Biochem. Biophys. Res. Commun.192, 1340 (1993). (10.1006/bbrc.1993.1563)
  41. In vitro immunosuppression was measured as the inhibition of IL-2-stimulated human CD4+ T cell proliferation.
  42. 10.1021/jm8012823, M. Abou-Gharbia. J. Med. Chem.52, 2 (2009). (10.1021/jm8012823)
  43. 10.1073/pnas.0710424105, B. Ruan, K. Pong, F. Jow, M. Bowlby, R. A. Crozier, D. Liu, S. Liang, Y. Chen, M. L. Mercado, X. Feng, F. Bennett, D. von Schack, L. McDonald, M. M. Zaleska, A. Wood, P. H. Reinhart, R. L. Magolda, J. Skotnicki, M. N. Pangalos, F. E. Koehn, G. T. Carter, M. Abou-Gharbia, E. I. Graziani. Proc. Natl. Acad. Sci. USA105, 33 (2008). (10.1073/pnas.0710424105)
  44. 10.1038/371336a0, J. Sharkey, S. P. Butcher. Nature371, 336 (1994). (10.1038/371336a0)
  45. Manuscript in preparation.
  46. B. G. Gold, V. Densmore, W. Shou, M. M. Matzuk, H. S. Gordon. J. Pharmacol. Exp. Ther.289, 1202 (1999).
Dates
Type When
Created 13 years, 2 months ago (June 7, 2012, 12:15 p.m.)
Deposited 3 years, 5 months ago (March 14, 2022, 9:47 a.m.)
Indexed 2 years, 3 months ago (May 20, 2023, 1:39 a.m.)
Issued 13 years, 2 months ago (June 7, 2012)
Published 13 years, 2 months ago (June 7, 2012)
Published Online 13 years, 2 months ago (June 7, 2012)
Published Print 13 years, 2 months ago (June 7, 2012)
Funders 0

None

@article{Abou_Gharbia_2012, title={Targeting neurodegenerative diseases: Drug discovery in a challenging arena}, volume={84}, ISSN={0033-4545}, url={http://dx.doi.org/10.1351/pac-con-11-11-09}, DOI={10.1351/pac-con-11-11-09}, number={7}, journal={Pure and Applied Chemistry}, publisher={Walter de Gruyter GmbH}, author={Abou-Gharbia, Magid and Childers, Wayne}, year={2012}, month=jun, pages={1543–1556} }