title: Design and synthesis of novel sulfonamide-containing bradykinin hB(2) 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.
authors.affiliation: Menarini Ricerche, Via Tito Speri 10, 10040 Pomezia, Rome, Italy.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Fincham
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bressan
authors.forename: Piero
authors.initials: P
authors.lastname: D'Andrea
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ettorre
authors.forename: Sandro
authors.initials: S
authors.lastname: Giuliani
authors.forename: Sandro
authors.initials: S
authors.lastname: Mauro
authors.forename: Stefania
authors.initials: S
authors.lastname: Meini
authors.forename: Marielle
authors.initials: M
authors.lastname: Paris
authors.forename: Laura
authors.initials: L
authors.lastname: Quartara
authors.forename: Cristina
authors.initials: C
authors.lastname: Rossi
authors.forename: Antonella
authors.initials: A
authors.lastname: Squarcia
authors.forename: Claudio
authors.initials: C
authors.lastname: Valenti
authors.forename: Fattori
authors.initials: F
authors.lastname: Daniela
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Maggi
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000378:metabolism; D065094:Bradykinin B2 Receptor Antagonists; D016084:Bronchoconstriction / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D007022:Hypotension / Q000188:drug therapy; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D065094:Bradykinin B2 Receptor Antagonists; D043782:Receptor, Bradykinin B2; D013449:Sulfonamides; D001920:Bradykinin; D005998:Glycine