title: Design and synthesis of novel sulfonamide-containing bradykinin hB2 receptor antagonists. 2. Synthesis and structure-activity relationships of alpha,alpha-cycloalkylglycine sulfonamides.
abstract: Recently we reported on the design and synthesis of a novel class of selective nonpeptide bradykinin (BK) B2 receptor antagonists (J. Med. Chem. 2006, 3602-3613). This work led to the discovery of MEN 15442, an antagonist with subnanomolar affinity for the human B2 receptor (hB2R), which also displayed significant and prolonged activity in vivo (for up to 210 min) against BK-induced bronchoconstriction in the guinea-pig at a dose of 300 nmol/kg (it), while demonstrating only a slight effect on BK-induced hypotension. Here we describe the further optimization of this series of compounds aimed at maximizing the effect on bronchoconstriction and minimizing the effect on hypotension, with a view to developing topically delivered drugs for airway diseases. The work led to the discovery of MEN 16132, a compound which, after intratracheal or aerosol administration, inhibited, in a dose-dependent manner, BK-induced bronchoconstricton in the airways, while showing minimal systemic activity. This compound was selected as a preclinical candidate for the topical treatment of airway diseases involving kinin B2 receptor stimulation.
authors.affiliation: Menarini Ricerche, Via Tito Speri 10, 00040 Pomezia (Rome), Italy. dfattori@menarini-ricerche.it
authors.forename: Daniela
authors.initials: D
authors.lastname: Fattori
authors.forename: Cristina
authors.initials: C
authors.lastname: Rossi
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Fincham
authors.forename: Valerio
authors.initials: V
authors.lastname: Caciagli
authors.forename: Fernando
authors.initials: F
authors.lastname: Catrambone
authors.forename: Piero
authors.initials: P
authors.lastname: D'Andrea
authors.forename: Patrizia
authors.initials: P
authors.lastname: Felicetti
authors.forename: Martina
authors.initials: M
authors.lastname: Gensini
authors.forename: Elena
authors.initials: E
authors.lastname: Marastoni
authors.forename: Rossano
authors.initials: R
authors.lastname: Nannicini
authors.forename: Marielle
authors.initials: M
authors.lastname: Paris
authors.forename: Rosa
authors.initials: R
authors.lastname: Terracciano
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bressan
authors.forename: Sandro
authors.initials: S
authors.lastname: Giuliani
authors.forename: Carlo A
authors.initials: CA
authors.lastname: Maggi
authors.forename: Stefania
authors.initials: S
authors.lastname: Meini
authors.forename: Claudio
authors.initials: C
authors.lastname: Valenti
authors.forename: Laura
authors.initials: L
authors.lastname: Quartara
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D065094:Bradykinin B2 Receptor Antagonists; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009952:Ornithine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C506838:(4-amino-5-(4-(4-(2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido)tetrahydro-2H-4-pyranoylcarbonyl)piperazino)-5-oxopentyl)(trimethyl)ammonium; D065094:Bradykinin B2 Receptor Antagonists; D001993:Bronchodilator Agents; D007295:Inositol Phosphates; D013449:Sulfonamides; D009952:Ornithine