Design and synthesis of fluorescent SGLT2 inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 18, 2008, Pages 4944-4947

  Lansdell, Mark I ^a   Burring, Denise J ^a   Hepworth, David ^a   Strawbridge, Matthew ^a   Graham, Emily ^a   Guyot, Thierry ^b   Betson, Mark S ^b   Hart, James D ^b  

^a PFIZER INC   (United States)

^b CXR Biosciences Ltd   (United Kingdom)

Author keywords

Conjugation; Fluorophore; Inhibitor; SGLT2

Indexed keywords

PHLORIZIN; PROTEIN INHIBITOR; SODIUM GLUCOSE COTRANSPORTER 2; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; CONTROLLED STUDY; DRUG DESIGN; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; FEMALE; FLUOROMETRY; IN VITRO STUDY; NONHUMAN; STRUCTURE ANALYSIS;

COMBINATORIAL CHEMISTRY TECHNIQUES; DRUG DESIGN; FLUORESCENT DYES; MOLECULAR STRUCTURE; PHLORHIZIN; SODIUM-GLUCOSE TRANSPORTER 2;

EID: 51749118676     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.08.036     Document Type: Article

References (36)

1. Wright E.M. Am. J. Physiol. Renal Physiol. 280 (2001) F10
2. Wright E.M., and Turk E. Pflugers Arch. Eur. J. Physiol. 447 (2004) 510
3. Wright E.M., Turk E., Hager K., Lescale-Matys L., Hirayama B., Supplisson S., and Loo D.D.F. Acta Physiol. Scand. Suppl. 607 (1992) 201
4. Wright E.M., Hirayama B., Hazama A., Loo D.D.F., Supplisson S., Turk E., and Hager K.M. Soc. Gen. Physiol. Ser. 48 (1993) 229
5. Wells R.G., Pajor A.M., Kanai Y., Turk E., Wright E.M., and Hediger M.A. Am. J. Physiol. 263 (1992) F459
6. Kanai Y., Lee W.-S., You G., Brown D., and Hediger M.A. J. Clin. Invest. 93 (1994) 397
7. van den Heuvel L.P., Assink K., Willemsen M., and Monnens L. Hum. Genet. 111 (2002) 544
8. Santer R., Kinner M., Lassen C.L., Schneppenheim R., Eggert P., Bald M., Brodehl J., Daschner M., Ehrich J.H.H., Kemper M., Volti S.L., Neuhaus T., Skovby F., Swift P.G.F., Schaub J., and Klaerke D. J. Am. Soc. Nephrol. 14 (2003) 2873
9. Francis J., Zhang J., Farhi A., Carey H., and Geller D.S. Nephrol. Dial. Transplant. 19 (2004) 2893
10. Kleta R., Stuart C., Gill F.A., and Gahl W.A. Mol. Genet. Metab. 82 (2004) 56
11. Magen D., Sprecher E., Zelikovic I., and Skorecki K. Kidney Int. 67 (2005) 34
12. Handlon A.L. Expert Opin. Ther. Patents 15 (2005) 1531
13. Isaji M. Curr. Opin. Invest. Drugs 8 (2007) 285
14. Ehrenkranz J.R.L., Lewis N.G., Kahn C.R., and Roth J. Diabetes Metab. Res. Rev. 21 (2005) 31
15. Katsuno K., Fujimori Y., Takemura Y., Hiratochi M., Itoh F., Komatsu Y., Fujikura H., and Isaji M. J. Pharmacol. Exp. Ther. 320 (2007) 323
16. Pajor A.M., Randolph K.M., Kerner S.A., and Smith C.D. J. Pharmacol. Exp. Ther. 324 (2008) 985
17. Meng W., Ellsworth B.A., Nirschl A.A., McCann P.J., Patel M., Girotra R.N., Wu G., Sher P.M., Morrison E.P., Biller S.A., Zahler R., Deshpande P.P., Pullockaran A., Hagan D.L., Morgan N., Taylor J.R., Obermeier M.T., Humphreys W.G., Khanna A., Discenza L., Robertson J.G., Wang A., Han S., Wetterau J.R., Janovitz E.B., Flint O.P., Whaley J.M., and Washburn W.N. J. Med. Chem. 51 (2008) 1145
18. Castaneda F., and Kinne R.K.-H. Mol. Cell. Biochem. 280 (2005) 91
19. Middleton R.J., and Kellam B. Curr. Opin. Chem. Biol. 9 (2005) 517
20. Hödl C., Strauss W.S.L., Sailer R., Seger C., Steiner R., Haslinger E., and Schramm H.W. Bioconjugate Chem. 15 (2004) 359
21. Xie S.-X., Petrache G., Schneider E., Ye Q.-Z., Bernhardt G., Seifert R., and Buschauer A. Bioorg. Med. Chem. Lett. 16 (2006) 3886
22. Cowart M., Gfesser G.A., Bhatia K., Esser R., Sun M., Miller T.R., Krueger K., Witte D., Esbenshade T.A., and Hancock A.A. Inflamm. Res. 55 (2006) S47
23. Middleton R.J., Briddon S.J., Cordeaux Y., Yates A.S., Dale C.L., George M.W., Baker J.G., Hill S.J., and Kellam B. J. Med. Chem. 50 (2007) 782
24. Amon M., Ligneau X., Camelin J.-C., Berrebi-Bertrand I., Schwartz J.-C., and Stark H. ChemMedChem 2 (2007) 708
25. Schneider E., Keller M., Brennauer A., Hoefelschweiger B.K., Gross D., Wolfbeis O.S., Bernhardt G., and Buschauer A. ChemBioChem 8 (2007) 1981
26. Singleton D.H., Boyd H., Steidl-Nichols J.V., Deacon M., de Groot M.J., Price D., Nettleton D.O., Wallace N.K., Troutman M.D., Williams C., and Boyd J.G. J. Med. Chem. 50 (2007) 2931
27. Jones L.H., Randall A., Napier C., Trevethick M., Sreckovic S., and Watson J. Bioorg. Med. Chem. Lett. 18 (2008) 825
28. Deacon M., Singleton D., Szalkai N., Pasieczny R., Peacock C., Price D., Boyd J., Boyd H., Steidl-Nichols J., and Williams C. J. Pharmacol. Toxicol. Methods 55 (2007) 255
29. The more ambitious approach of incorporating the fluorophore within the minimum pharmacophore to actively contribute to SGLT2-inhibition was briefly explored, but was found to be insufficiently promising.
30. Eckhardt, M.; Eickelmann, P.; Himmelsbach, F.; Barsoumian, E. L.; Leo, T. WO2005092877.
31. All fluorophores were purchased from Invitrogen (Molecular Probes), with the exception of Cy3B NHS ester and NBD chloride, which were purchased from GE Healthcare and Sigma-Aldrich, respectively.
32. The structure of dapagliflozin 3 had not been disclosed by the time this work was completed. We had employed close-analogue 4 (Washburn W.; Meng W. US20060063722), alongside phlorizin 1, to benchmark our SGLT2 assay. In a later, slightly modified, format of the assay, we have since established that 3 and 4 are equipotent.
33. Methodology analogous to that described for SGLT1 by:. Lin J.-T., Kormanec J., Wehner F., Wielert-Badt S., and Kinne R.K.-H. Biochim. Biophys. Acta 1373 (1998) 309
34. Adlington R.M., Baldwin J.E., Becker G.W., Chen B., Cheng L., Cooper S.L., Hermann R.B., Howe T.J., McCoull W., McNulty A.M., Neubauer B.L., and Pritchard G.J. J. Med. Chem. 44 (2001) 1491
35. 2 (g) in the freezer until purification, which was performed by preparative HPLC.
36. The excitation-emission profiles of compounds 23d, 27a, and 28b were measured and found to be essentially unchanged from the corresponding commercially available fluorophore precursors.