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Document Figure 8 (a) Binding assay results for 10 original nonpeptidic libraries of the sequence DArg-Arg-X-Y-Arg, where X and Y are defined as PH = phenanthridinone, CB = carboline, SP = spirocycle, SC = straight chain, CN = cinnamic acid. Each library was tested at 1 μnM and 10 nM. Results were compared to cold bradykinin binding, which was tested at two lower concentrations, 0.1 nM and 1 nM. Panels (b) and (c) correspond to the receptor binding results obtained using the two breakdown steps from original library number 1, as shown in Figure 9. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_143.html (2 of 2) [4/5/2004 5:00:18 PM]
Document Figure 9 Composition of ten original nonpeptidic libraries of the sequence DArg-Arg-X-Y-Arg. X and Y were selected from the set of scaffolds shown in Table 1. Also shown are the subsequent breakdown libraries from original library number 1. Two-letter codes used in the figure correspond to the different nonpeptide moieties described in Table 1. Specifically, PH = phenanthridinone, CB = carboline, SP = spirocycle, SC = Straight chain, CN = cinnamic acid. Page 144 four novel nonpeptidic structures showed that only one of the four had affinity to the receptor (Figure 8c). This new compound, I, was subsequently shown to be an antagonist in a cellular assay measuring bradykinin-stimulated IP turnover [18]. Overall, there were 285 possible structures to survey due to the number of structure-<strong>based</strong> scaffolds that were prepared. This was rapidly accomplished via 19 synthetic couplings, 19 assays, and 4 purifications. Not surprisingly, compound I showed divergent potency when assayed in different species homologues of the bradykinin B2 receptor. In particular, in a model of bradykinin-induced hypotension in rats and rabbits, it showed no activity. Likewise, it did not block bradykinin-induced contraction of the isolated guinea pig ileum. Since compound I is considerably smaller than previously reported decapeptide antagonists, subtle structural differences (which are http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_144.html (1 of 2) [4/5/2004 5:00:24 PM]
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Page 149 and 150: Document 4 Bradykinin Receptor Anta
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Document Table 1 Approval Indicatio
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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