Design and synthesis of novel sulfonamide-containing bradykinin hB2 receptor antagonists. Synthesis and structure-relationships of α,α-tetrahydropyranylglycine

Abstract A series of α,α-cycloalkylglycine sulfonamide compounds of general formula 1 has previously been identified by our group as selective human B 2 (hB 2 ) receptor antagonists. Here we report the in vitro and in vivo BK antagonist activity of a further evolution of the series, consisting in compounds of the general formula 2 , containing either an alkyl piperazine or a 4-alkyl piperidine ring bearing various positively charged groups (R′). These studies unexpectedly revealed quite a flat nanomolar/subnanomolar SAR for the binding affinity, while differences were seen in the in vitro functional activities. We propose that variations in the residence time may explain these results.