A new class of bradykinin 1 receptor antagonists containing the piperidine acetic acid tetralin core

The bradykinin 1 (B1) receptor is upregulated during times of inflammation and is important for maintaining inflamed and chronic pain states. Blocking this receptor has been shown to reverse and/or ameliorate pain and inflammation in animal models. In this report, we describe a new class of B1 receptor antagonists that contain the piperidine acetic acid tetralin core. A structure–activity relationship for these analogs is described in this paper. The most potent compounds from this class have IC50s < 20 nM in a B1 receptor functional assay. One of these compounds, 13g, shows modest oral bioavailability in rats.

Compound 1 was an early lead in our bradykinin 1 receptor antagonist program. By adding two conformational constraints to this compound and by exploring the SAR of the aryl sulfonamide and terminal amine groups, we identified compound 13g, which was 220-fold more potent than compound 1 and selective over the bradykinin 2 receptor.Figure optionsDownload as PowerPoint slide