A structurally distinct chemotype of UT antagonists is represented by the tetrahydrobenzazepines 27 also reported in a patent application by Japanese workers (56). The compounds disclosed are among the most potent U-ll antagonists known (e.g. 27, IC5o = 1.7 nM for the inhibition of U-ll binding to hUT) and are alleged to be inhibitors of vasoconstriction and hence likely to be useful for the treatment of cardiovasular disorders. Similarly, the biphenyldicarboxamide scaffold represented by the general structure 28, has also provided highly potent UT antagonists (IC5o -10 nM) that additionally incorporate high somatostatin (SST5 IC5o -5 nM) receptor affinity (57).
As mentioned above, U-ll and UT share some primary sequence similarity at both the ligand and receptor level to somatostatin and the SST receptors. Importantly however, neither somatostatin nor U-ll show any affinity for UT or the SST receptors respectively. By virtue of combining UT and SST5 antagonism, amongst other indications, these compounds are claimed to be useful as combined antihypertensives and antidiabetic agents.
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