Nonpeptide Bradykinin B1 Receptor Antagonists

Interest in the development of non-peptide bradykinin B1 antagonists is slowly producing results. While the availability of these compounds has been anticipated for some time, reports describing non-peptide B1 antagonists have only recently appeared. The first small molecule B1 antagonists were disclosed in a 1997 patent application and as they retain considerable peptide character are more properly termed dipeptidomimetics (77). One of the prototypical compounds (7) is comprised of an N-(arylsulfonyl)-p-amino acid and a phenyl alanine amide with R the preferred configuration at both asymmetric centers. The affinity of 7 for B1 receptors was found to be in the 10 M range as measured on a suspension of MRC5 cell membranes. The affinity for the B2 receptors was between 10"7 to 10"6 M. A more recent patent application claims close molecular analogs of 7. A preferred structure covered in this application is 8 (78). Based on the exquisite B1 receptor binding affinity of 7, it can be assumed that modifications to this structure (cf. 8) were made only to fine tune pharmacokinetic and/or physical properties. No supporting data for 8 or its analogs have been disclosed.


The arylsulfonamides 9 and 10 were described in the patent literature a few years ago and displayed potency in a receptor binding assay employing membranes derived from HEK 293 cells expressing the cloned human B1 receptor (79). K, values ranging to as low as 0.5 nM were reported. The functional activity of these compounds was demonstrated in a primate model of thermal antlnociception. In this test, the exemplified compounds were effective in preventing or reversing carrageenan-induced hyperalgesia at a dosage of 10 nmol/kg.

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