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known to exist in species homologs of the bradykinin B2 receptor) are likely amplified. A more
comprehensive pharmacological analysis of compound I is currently underway.
A. Lead Optimization
Page 145
We have previously reported that the C-terminal guanidinyl moiety of Arg [9] in prototypical peptide
bradykinin antagonists is likely to behave more as an aromatic functional group rather than a hydrogenbond
donor/acceptor. This speculation was based on proposed models of the agonist and antagonist
binding sites of this receptor that have been elucidated using molecular biological and computational
procedures. On this premise, the newly discovered lead compound, I, was altered such that the Cterminal
arginine was replaced by 3',5'-dimethylpyrimidylornithine in an attempt to increase potency.
This known mimetic of arginine contains an aromatic 3',5'-dimethylpyrimidyl ring in the side chain
rather than the guanidino group on naturally occurring arginine.
The results of the receptor binding assay performed using this compound, IA, are shown in Table 4
where it is clear that affinity to the human B2 receptor is improved with respect to compound I. This
data is supportive of the notion that the C-terminal residue(s) in this new series of bradykinin antagonist
compounds interact with a hydrophobic environment, perhaps within the transmembrane domain of the
receptor as previously suggested.
The discovery of I and IA is significant in many regards. First, they are highly nonpeptidic lead
compounds that could be further modified to improve potency and/or reduce molecular weight. Such
improvements might lead to novel therapeutic agents for the treatment of inflammatory diseases. Thus
far in the kinin antagonist literature there is significant evidence showing that, for compounds containing
a C-terminal arginine residue, removal of that arginine generally yields compounds that are antagonists
of the B1 subtype of the bradykinin receptor. Following a similar strategy with compound I could lead to
the discovery of a novel series of nonpeptidic B1 receptor antagonists, although this remains to be
demonstrated.
V. Conclusions
There has been a significant effort invested toward the discovery of novel bradykinin receptor
antagonists during the past decade. In that time, several generations of peptide antagonists have been
developed and a few are in human clinical trials. The pursuit of nonpeptide antagonists of the human
bradykinin B2 receptor continues and incorporates a wide range of strategic approaches. The approach
described herein is an early and very good example of a combinatorial synthesis of nonpeptide building
blocks that mimic peptide structure,
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