Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain

Journal of Lipid Research

Volumn 53, Issue 2, 2012, Pages 282-291

  Larsen, Scott D ^a   Wilson, Michael W ^a   Abe, Akira ^b   Shu, Liming ^b   George, Christopher H ^a   Kirchhoff, Paul ^a   Showalter, H D Hollis ^a   Xiang, Jianming ^b   Keep, Richard F ^b   Shayman, James A ^a  

^a UNIVERSITY OF MICHIGAN   (United States)

^b UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

Author keywords

Blood brain barrier; Eliglustat tartrate; Gaucher disease; Glycosphingolipid; Synthesis inhibition therapy

Indexed keywords

2 (2,3 DIHYDRO 1H INDEN 2 YL) N 1 (2,3 DIHYDROBENZO[B][1,4]DIOXIN 6 YL) 1 HYDROXY 3 (PYRROLIDIN 1 YL)PROPAN 2 YL ACETAMIDE; CCG 203586; CERAMIDE GLUCOSYLTRANSFERASE INHIBITOR; ELIGLUSTAT; GLUCOSYLCERAMIDE; MULTIDRUG RESISTANCE PROTEIN 1; UNCLASSIFIED DRUG; VINBLASTINE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BRAIN TISSUE; CELL STRAIN; CONTROLLED STUDY; DOSE RESPONSE; DRUG ACTIVITY; DRUG DESIGN; DRUG MECHANISM; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ACTIVITY; ENZYME INHIBITION; FEMALE; IN VIVO STUDY; KIDNEY PARENCHYMA; LIPID ANALYSIS; LIVER; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL;

ANIMALS; BRAIN; CELLS, CULTURED; DIOXANES; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; ENZYME INHIBITORS; GLUCOSYLCERAMIDES; GLUCOSYLTRANSFERASES; INDANS; INJECTIONS, INTRAPERITONEAL; MICE; MICE, INBRED C57BL; MORPHOLINES; P-GLYCOPROTEIN; VINBLASTINE;

EID: 84863399238     PISSN: 00222275     EISSN: 15397262     Source Type: Journal    
DOI: 10.1194/jlr.M021261     Document Type: Article

References (30)

1. Barton, N. W., R. O. Brady, J. M. Dambrosia, A. M. Di Bisceglie, S. H. Doppelt, S. C. Hill, H. J. Mankin, G. J. Murray, R. I. Parker, C. E. Argoff, et al. 1991. Replacement therapy for inherited enzyme deficiency-macrophage- targeted glucocerebrosidase for Gaucher's disease. N. Engl. J. Med. 324: 1464-1470.
2. Radin, N. S. 1996. Treatment of Gaucher disease with an enzyme inhibitor. Glycoconj. J. 13: 153-157. (Pubitemid 26132722)
3. Shayman, J. A., L. Lee, A. Abe, and L. Shu. 2000. Inhibitors of glucosylceramide synthase. Methods Enzymol. 311: 373-387. (Pubitemid 29512781)
4. Weinreb, N. J., J. A. Barranger, J. Charrow, G. A. Grabowski, H. J. Mankin, and P. Mistry. 2005. Guidance on the use of miglustat for treating patients with type 1 Gaucher disease. Am. J. Hematol. 80: 223-229. (Pubitemid 41579546)
5. Shayman, J. A. 2010. Eliglustat tartrate. Drugs Future. 35: 613-621.
6. Lukina, E., N. Watman, E. A. Arreguin, M. Banikazemi, M. Dragosky, M. Iastrebner, H. Rosenbaum, M. Phillips, G. M. Pastores, D. I. Rosenthal, et al. 2010. A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1. Blood. 116: 893-899.
7. Abe, A., S. Gregory, L. Lee, P. D. Killen, R. O. Brady, A. Kulkarni, and J. A. Shayman. 2000. Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation. J. Clin. Invest. 105: 1563-1571. (Pubitemid 30390307)
8. Liu, Y., R. Wada, H. Kawai, K. Sango, C. Deng, T. Tai, M. P. McDonald, K. Araujo, J. N. Crawley, U. Bierfreund, et al. 1999. A genetic model of substrate deprivation therapy for a glycosphingo-lipid storage disorder. J. Clin. Invest. 103: 497-505. (Pubitemid 29094050)
9. Miller, D. S. 2010. Regulation of P-glycoprotein and other ABC drug transporters at the blood-brain barrier. Trends Pharmacol. Sci. 31: 246-254.
10. Hirth, B. H., and C. Siegel. 2005. Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors. Patent no. 6,855,830. Genzyme Corporation, United States.
11. Shayman, J. A., and A. Abe. 2000. Glucosylceramide synthase: assay and properties. Methods Enzymol. 311: 42-49. (Pubitemid 29512749)
12. Shu, L., and J. A. Shayman. 2003. Src kinase mediates the regulation of phospholipase C-gamma activity by glycosphingolipids. J. Biol. Chem. 278: 31419-31425. (Pubitemid 36994663)
13. Shu, C., H. Shen, N. S. Teuscher, P. J. Lorenzi, R. F. Keep, and D. E. Smith. 2002. Role of PEPT2 in peptide/mimetic trafficking at the blood-cerebrospinal fluid barrier: studies in rat choroid plexus epithelial cells in primary culture. J. Pharmacol. Exp. Ther. 301: 820-829. (Pubitemid 34595070)
14. Wishart, D. S., C. Knox, A. C. Guo, D. Cheng, S. Shrivastava, D. Tzur, B. Gautam, and M. Hassanali. 2008. DrugBank: a knowledge-base for drugs, drug actions and drug targets. Nucleic Acids Res. 36: D901-D906. (Pubitemid 351149842)
15. Jimbo, M., K. Yamagishi, T. Yamaki, K. Nunomura, K. Kabayama, Y. Igarashi, and J. I. Inokuchi. 2000. Development of a new inhibitor of glucosylceramide synthase. J. Biochem. 127: 485-491. (Pubitemid 30185254)
16. Lee, L., A. Abe, and J. A. Shayman. 1999. Improved inhibitors of glucosylceramide synthase. J. Biol. Chem. 274: 14662-14669.
17. Lipinski, C. A., F. Lombardo, B. W. Dominy, and P. J. Feeney. 2001. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46: 3-26. (Pubitemid 33653411)
18. Garberg, P., M. Ball, N. Borg, R. Cecchelli, L. Fenart, R. D. Hurst, T. Lindmark, A. Mabondzo, J. E. Nilsson, T. J. Raub, et al. 2005. In vitro models for the blood-brain barrier. Toxicol. In Vitro. 19: 299-334. (Pubitemid 40248750)
19. Wang, Q., J. D. Rager, K. Weinstein, P. S. Kardos, G. L. Dobson, J. Li, and I. J. Hidalgo. 2005. Evaluation of the MDR-MDCK cell line as a permeability screen for the blood-brain barrier. Int. J. Pharm. 288: 349-359. (Pubitemid 40038588)
20. Gouaze-Andersson, V., and M. C. Cabot. 2006. Glycosphingo-lipids and drug resistance. Biochim. Biophys. Acta. 1758: 2096-2103.
21. Mahar Doan, K. M., J. E. Humphreys, L. O. Webster, S. A. Wring, L. J. Shampine, C. J. Serabjit-Singh, K. K. Adkison, and J. W. Polli. 2002. Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J. Pharmacol. Exp. Ther. 303: 1029-1037. (Pubitemid 35424386)
22. Leeson, P. D., and A. M. Davis. 2004. Time-related differences in the physical property profiles of oral drugs. J. Med. Chem. 47: 6338-6348. (Pubitemid 39587257)
23. Pajouhesh, H., and G. R. Lenz. 2005. Medicinal chemical properties of successful central nervous system drugs. NeuroRx. 2: 541-553. (Pubitemid 41393264)
24. Cecchelli, R., V. Berezowski, S. Lundquist, M. Culot, M. Renftel, M. P. Dehouck, and L. Fenart. 2007. Modelling of the blood-brain barrier in drug discovery and development. Nat. Rev. Drug Discov. 6: 650-661. (Pubitemid 47202487)
25. Lundquist, S., M. Renftel, J. Brillault, L. Fenart, R. Cecchelli, and M. P. Dehouck. 2002. Prediction of drug transport through the blood-brain barrier in vivo: a comparison between two in vitro cell models. Pharm. Res. 19: 976-981. (Pubitemid 34804239)
26. Raub, T. J. 2006. P-glycoprotein recognition of substrates and circumvention through rational drug design. Mol. Pharm. 3: 3-25. (Pubitemid 43331747)
27. Ito, S., C. Woodland, B. Sarkadi, G. Hockmann, S. E. Walker, and G. Koren. 1999. Modeling of P-glycoprotein-involved epithelial drug transport in MDCK cells. Am. J. Physiol. 277: F84-F96. (Pubitemid 29352678)
28. Kuteykin-Teplyakov, K., C. Luna-Tortos, K. Ambroziak, and W. Loscher. 2010. Differences in the expression of endogenous effl ux transporters in MDR1-transfected versus wildtype cell lines affect P-glycoprotein mediated drug transport. Br. J. Pharmacol. 160: 1453-1463.
29. Abe, A., M. Hiraoka, and J. A. Shayman. 2007. A role for lysosomal phospholipase A2 in drug induced phospholipidosis. Drug Metab Lett. 1: 49-53.
30. Mazzulli, J. R., Y. H. Xu, Y. Sun, A. L. Knight, P. J. McLean, G. A. Caldwell, E. Sidransky, G. A. Grabowski, and D. Krainc. 2011. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 146: 37-52.