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N.; Giaid, A. Lancet 2002, 359, 1990; (b) Ng, L. L.; Loke,
I.; OÕBrien, R. J.; Squire, I. B.; Davies, J. E. Circulation
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Figure 2. Structure of truncated analog SB-436811 (1a).
to the binding affinity difference between primate and
rodent receptors, the significant sequence differences be-
tween primate and rodent receptors3 might be a reason
for the observed receptor binding affinity difference.
In summary, a novel hU-II receptor antagonist series
represented by SB-328872 (2a) was identified via HTS.
The SAR was explored for several regions of this series
and that led to the identification of a novel truncated
sub-series represented by SB-436811 (1a). Further opti-
mization of other regions, especially the right-hand
side aminoalkoxybenzyl and central aminopyrrolidine
moieties, of both series will be the subject of future
publications.
14. (a) Totsune, K.; Takahashi, K.; Arihara, Z.; Sone, M.;
Satoh, F.; Ito, S.; Murakami, O. Clin. Sci. 2003, 104, 1; (b)
Wenyi, Z.; Suzuki, S.; Hirai, M.; Hinokio, Y.; Tanizawa,
Y.; Matsutani, A.; Satoh, J.; Oka, Y. Diabetologia 2003,
46, 972.
Acknowledgments
15. (a) Flohr, S.; Kurz, M.; Kostenis, E.; Brkovich, A.;
Fournier, A.; Klabunde, T. J. Med. Chem. 2002, 45, 1799;
(b) Croston, G. E.; Olsson, R.; Currier, E. A.; Burstein, E.
S.; Weiner, D.; Nash, N.; Severance, D.; Allenmark, S. G.;
Thunberg, L.; Ma, J.; Mohell, N.; OÕDowd, B.; Brann, M.
R.; Hacksell, U. J. Med. Chem. 2002, 45, 4950(c) For
patents, see Ref. 3.
We thank Chad Quinn and Qian Jin for providing
analytical LC/MS support.
References and notes
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the primary assay to generate SAR.
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19. Purchased from TCI America, catalog number: A1172 or
A1171.
20. Purchased from Polymer Laboratories, part number:
1466-6689, 150–300 lM, 1.5 mmol/g loading.
21. Purchased from Novabiochem.
22. Confirmed via NMR studies. All new compounds in this
paper were characterized via LC/MS and/or H NMR.
1
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