S. Nordhoff et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6340–6345
6345
10. Nordhoff, S.; López-Canet, M.; Hoffmann-Enger, B.; Bulat, S.; Cerezo-Gálvez, S.;
Hill, O.; Rosenbaum, C.; Rummey, C.; Thiemann, M.; Matassa, V. G.; Edwards, P.
J.; Feurer, A. Bioorg. Med. Chem. Lett. 2009, 19, 4818.
evaluation is focused on preclinical safety and more comprehen-
sive efficacy profiling. Results will be reported in due course.
11. Experimental details and data on the characterisation of compounds can be
found in: WO2005/121131.For details on the DPP-4 inhibition assay please
see: Ref. 17.
Acknowledgments
12. (a) Wadsworth, H. J.; Jenkins, S. M.; Orlek, B. S.; Cassidy, F.; Clark, M. S. G.;
Brown, F.; Riley, G. J.; Graves, D.; Hawkins, J.; Naylor, C. B. J. Med. Chem. 1992,
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B. M. J. Med. Chem. 1978, 21, 1254.
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14. (a) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett. 2000, 2,
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The authors are grateful to Julia Seiler, Bettina Cardel, Ute Sch-
mitt, Tina Pfeiffer-Unckrich and Siglinde Zepter for excellent tech-
nical assistance. We thank Bernd Löffler and Judith Dubach-Powell
for helpful discussions.
Supplementary data
15. Falorni, M.; Giacomelli, G.; Spanedda, A. M. Tetrahedron: Asymmetry 1998, 3039,
9.
16. For a one-pot procedure for the synthesis of alkynes from aldehydes, step (a),
see: Roth, G. H.; Liepold, B.; Müller, S. G.; Bestmann, H. J. Synthesis 2004, 1, 59;
for step (b), see: Liu, Q.; Tor, Y. Org. Lett. 2003, 5, 2571; the assignment of
isomers was performed according to NMR analysis, see: Tornoe, C. W.;
Christiensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
17. A detailed assay description can be found in: Nordhoff, S.; Cerezo-Gálvez, S.;
Feurer, A.; Hill, O.; Matassa, V. G.; Metz, G.; Rummey, C.; Thiemann, M.;
Edwards, P. J. Bioorg. Med. Chem. Lett. 2006, 16, 1744.
Supplementary data associated with this article can be found, in
References and notes
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20. Details on the ADME assays can be found in Ref. 10.
21. Compounds 6c, 6m, and 7c exhibit low to moderate ppb (rat), 7f shows very
low ppb.
22. Compound (3 mg/kg) or vehicle was administered po to ob/ob mice 30 min
prior to an oral glucose challenge of 1 g/kg. Time points for blood glucose
measurement were À30 (shortly prior to the administration of test item); 0, 15,
30, 60, 90, and 180 min after glucose application. Data are expressed as
mean SEM (n = 12/group). The blood glucose lowering effect of MK-0431 is
comparable to 6m and 7f in this experiment. % Inhibition of plasma DPP-4
activity in an assay containing 80% mouse plasma at 60 and 180 min was found
to be 79 5 and 64 7 for 6m and 70 3 and 56 5 for 7f.
9. Nordhoff, S.; Cerezo-Gálvez, S.; Deppe, H.; Hill, O.; López-Canet, M.; Rummey,
C.; Thiemann, M.; Matassa, V. G.; Edwards, P. J.; Feurer, A. Bioorg. Med. Chem.
Lett. 2009, 19, 4201.